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1
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Yang WL, Zhou XY, Jiang WC, Zhang XJ, Zhou D. Opioid analgesics for sedation-based gastrointestinal endoscopy. World J Gastrointest Pharmacol Ther 2025; 16:102098. [DOI: 10.4292/wjgpt.v16.i2.102098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 01/13/2025] [Accepted: 03/04/2025] [Indexed: 06/03/2025] Open
Abstract
Gastrointestinal endoscopy is a common examination for digestive system. The stimulation of endoscope often causes cough, nausea and vomiting, increased heart rate and blood pressure, arrhythmia, and even cardiovascular and cerebrovascular accidents, thus makes people fear of this procedure. Sedation or anesthesia can effectively improve the safety, comfort and quality of gastrointestinal endoscopy. A small dose of opioids is a good adjuvant to sedatives. In this narrative review, we summarized the main roles of opioid analgesics in gastrointestinal endoscopy, including reducing visceral pain, throat irritation and the dose of sedatives. Moreover, the frequently used and novel opioids are reviewed. Classic fentanyl, sufentanil and dezocine are preferable by anesthesiologists. Newly approved oliceridine is promising to render ideal analgesic effects for gastrointestinal endoscopy. Clinical studies on oliceridine in endoscopic procedures are urgently needed.
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Affiliation(s)
- Wei-Lin Yang
- Department of Anesthesiology, Deyang People’s Hospital, Deyang 618000, Sichuan Province, China
- Graduate School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan Province, China
| | - Xin-Yu Zhou
- Department of Anesthesiology, Deyang People’s Hospital, Deyang 618000, Sichuan Province, China
- Graduate School, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Wen-Cai Jiang
- Department of Anesthesiology, Deyang People’s Hospital, Deyang 618000, Sichuan Province, China
| | - Xian-Jie Zhang
- Department of Anesthesiology, Deyang People’s Hospital, Deyang 618000, Sichuan Province, China
| | - Dan Zhou
- Department of Anesthesiology, Deyang People’s Hospital, Deyang 618000, Sichuan Province, China
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2
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Conflitti P, Lyman E, Sansom MSP, Hildebrand PW, Gutiérrez-de-Terán H, Carloni P, Ansell TB, Yuan S, Barth P, Robinson AS, Tate CG, Gloriam D, Grzesiek S, Eddy MT, Prosser S, Limongelli V. Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery. Nat Rev Drug Discov 2025; 24:251-275. [PMID: 39747671 PMCID: PMC11968245 DOI: 10.1038/s41573-024-01083-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2024] [Indexed: 01/04/2025]
Abstract
G protein-coupled receptors (GPCRs) are the largest human membrane protein family that transduce extracellular signals into cellular responses. They are major pharmacological targets, with approximately 26% of marketed drugs targeting GPCRs, primarily at their orthosteric binding site. Despite their prominence, predicting the pharmacological effects of novel GPCR-targeting drugs remains challenging due to the complex functional dynamics of these receptors. Recent advances in X-ray crystallography, cryo-electron microscopy, spectroscopic techniques and molecular simulations have enhanced our understanding of receptor conformational dynamics and ligand interactions with GPCRs. These developments have revealed novel ligand-binding modes, mechanisms of action and druggable pockets. In this Review, we highlight such aspects for recently discovered small-molecule drugs and drug candidates targeting GPCRs, focusing on three categories: allosteric modulators, biased ligands, and bivalent and bitopic compounds. Although studies so far have largely been retrospective, integrating structural data on ligand-induced receptor functional dynamics into the drug discovery pipeline has the potential to guide the identification of drug candidates with specific abilities to modulate GPCR interactions with intracellular effector proteins such as G proteins and β-arrestins, enabling more tailored selectivity and efficacy profiles.
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Affiliation(s)
- Paolo Conflitti
- Euler Institute, Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Lugano, Switzerland
| | - Edward Lyman
- Department of Physics and Astronomy, University of Delaware, Newark, DE, USA
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
| | - Mark S P Sansom
- Department of Biochemistry, University of Oxford, Oxford, UK
| | - Peter W Hildebrand
- Institute of Medical Physics and Biophysics, Faculty of Medicine, Leipzig University, Leipzig, Germany
| | - Hugo Gutiérrez-de-Terán
- Department of Cell and Molecular Biology, Uppsala University, Biomedical Centre, Uppsala, Sweden
| | - Paolo Carloni
- INM-9/IAS-5 Computational Biomedicine, Forschungszentrum Jülich, Jülich, Germany
- Department of Physics, RWTH Aachen University, Aachen, Germany
| | - T Bertie Ansell
- Department of Biochemistry, University of Oxford, Oxford, UK
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Shuguang Yuan
- Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Patrick Barth
- Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Anne S Robinson
- Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA
| | | | - David Gloriam
- Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark
| | - Stephan Grzesiek
- Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, Basel, Switzerland
| | - Matthew T Eddy
- Department of Chemistry, College of Liberal Arts and Sciences, University of Florida, Gainesville, FL, USA
| | - Scott Prosser
- Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada
| | - Vittorio Limongelli
- Euler Institute, Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Lugano, Switzerland.
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3
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Liu X, Deng C, Deng Y, Luo X, Zhang W. Molecule-rich solutions for achieving novel non-opioid analgesics. Drug Discov Today 2025; 30:104329. [PMID: 40081520 DOI: 10.1016/j.drudis.2025.104329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 02/28/2025] [Accepted: 03/07/2025] [Indexed: 03/16/2025]
Abstract
Despite their efficacy, opioids have long been associated with risks of addiction, tolerance, and dependence, leaving an unmet clinical need for pain treatment. Efforts have been devoted to developing novel classes of pain-relieving medication that outperform current options in terms of pain relief, side-effect profiles, and potential for abuse, but with limited success. Recent advances in the neurobiology of pain have shed light on the potential of targeting non-opioid receptors involved in pain processing. In this review, we identify avenues, ranging from molecular-based approaches to molecule-rich solutions, for effectively identifying non-opioid analgesics free from the side effects associated with opioids.
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Affiliation(s)
- Xingxing Liu
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Chaoyi Deng
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research, Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yu Deng
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research, Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xudong Luo
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Pharmacy, West China Tianfu Hospital, Sichuan University, Chengdu 610213, China
| | - Wensheng Zhang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research, Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China.
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4
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Luo JC, Lu S, Fu XL, Shen J, He HL, Pan C, Huang XB. Comparison of Oliceridine to Remifentanil for Optimal Analgesia in Mechanical Ventilation (CO-ROAM): Study Protocol for a Multicenter Randomized Controlled Trial. Pain Ther 2024; 13:1695-1704. [PMID: 39424775 PMCID: PMC11543959 DOI: 10.1007/s40122-024-00669-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 09/30/2024] [Indexed: 10/21/2024] Open
Abstract
INTRODUCTION Critically ill patients often endure pain, a distressing experience that can trigger diverse pathophysiological consequences. While remifentanil, with its rapid kinetics, is commonly used for analgesia in intensive care units (ICU), it frequently leads to opioid-related adverse effects. A promising alternative has emerged in oliceridine, a novel G protein-biased μ-opioid receptor agonist. This new drug offers the potential for effective pain relief with fewer side effects. However, its efficacy and safety profile in mechanically ventilated ICU patients remain to be fully elucidated. METHODS This is a multicenter, prospective, randomized, single-blind, active-controlled trial conducted across 24 ICUs in China. A total of 292 mechanically ventilated patients requiring analgesia and sedation will be randomly assigned in a 1:1 ratio to either the oliceridine or remifentanil group. The oliceridine group will receive oliceridine (2-20 μg/kg/h), while the remifentanil group will receive remifentanil (1.5-12 μg/kg/h). Both groups will receive propofol for sedation if necessary. The target for analgesia is Critical-Care Pain Observation Tool (CPOT) < 3, and for sedation is Richmond Agitation-Sedation Scale (RASS) - 2 to 0. PLANNED OUTCOMES The primary outcome will be the percentage of time within target analgesia during study drug administration. Secondary outcomes will include gastrointestinal dysfunction, respiratory depression, sedative usage, mechanical ventilation duration, ICU stay length, extubation failure rate, etc. TRIAL REGISTRATION: NCT06454292. Registered on June 11, 2024.
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Affiliation(s)
- Jing-Chao Luo
- Department of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Sen Lu
- Department of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xi-Liang Fu
- Department of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Jun Shen
- Department of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Hong-Li He
- Department of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Chun Pan
- Department of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
| | - Xiao-Bo Huang
- Department of Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
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5
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Du YD, Ma LL, Wu CY, Wu RH, Yu ZC, Zhou Y, Yang DS, Wu YD, Wang JG, Wu AX. Synthesis of 6- oxa-Spiro[4.5]decane Derivatives by Merging Ring-Opening of Benzo[ c]oxepines and Formal 1,2-Oxygen Migration. J Org Chem 2024; 89:15953-15963. [PMID: 39413407 DOI: 10.1021/acs.joc.4c02206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2024]
Abstract
A facile one-pot synthetic method has been developed for constructing 6-oxa-spiro[4.5]decane skeletons by merging the ring-opening of benzo[c]oxepines and formal 1,2-oxygen migration reactions. More than 30 examples of the 6-oxa-spiro[4.5]decane derivatives have been synthesized under transition-metal-free conditions.
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Affiliation(s)
- Yong-Dong Du
- School of Chemical Engineering, Guizhou Minzu University, Guizhou, Guiyang 550025, P. R. China
| | - Lin-Lin Ma
- School of Chemical Engineering, Guizhou Minzu University, Guizhou, Guiyang 550025, P. R. China
| | - Chun-Yan Wu
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - Rong-He Wu
- School of Chemical Engineering, Guizhou Minzu University, Guizhou, Guiyang 550025, P. R. China
| | - Zhi-Cheng Yu
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - You Zhou
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - Dong-Sheng Yang
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - Yan-Dong Wu
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - Jun-Gang Wang
- School of Chemical Engineering, Guizhou Minzu University, Guizhou, Guiyang 550025, P. R. China
| | - An-Xin Wu
- State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
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6
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Rullo L, Morosini C, Lacorte A, Cristani M, Coluzzi F, Candeletti S, Romualdi P. Opioid system and related ligands: from the past to future perspectives. JOURNAL OF ANESTHESIA, ANALGESIA AND CRITICAL CARE 2024; 4:70. [PMID: 39390585 PMCID: PMC11468104 DOI: 10.1186/s44158-024-00201-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 09/06/2024] [Indexed: 10/12/2024]
Abstract
Chronic pain is a pathological condition affecting about 30% of population. It represents a relevant social-health issue worldwide, and it is considered a significant source of human suffering and disability, strongly affecting patients' quality of life. Despite several pharmacological strategies to guarantee an adequate pain management have been proposed over the years, opioids still represent one of the primary choices for treating moderate-to-severe pain in both cancer and non-cancer patients. However, chronic use of opioids often leads to numerous side effects, including respiratory depression, constipation, analgesic tolerance, and opioid-induced hyperalgesia (OIH), which can strongly limit their use. Given the fundamental role of opioid system in pain relief, this review provides a general overview about the main actors (endogenous opioid peptides and receptors) involved in its modulation. Furthermore, this review explores the action and the limitations of conventional clinically used opioids and describes the efficacy and safety profile of some promising analgesic compounds. A deeper understanding of the molecular mechanisms behind both analgesic effects and adverse events could advance knowledge in this field, thus improving chronic pain treatment.
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Affiliation(s)
- Laura Rullo
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Irnerio 48, Bologna, 40126, Italy
| | - Camilla Morosini
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Irnerio 48, Bologna, 40126, Italy
| | - Antonio Lacorte
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Irnerio 48, Bologna, 40126, Italy
| | - Marco Cristani
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Irnerio 48, Bologna, 40126, Italy
| | - Flaminia Coluzzi
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, Rome, Italy
- Unit of Anaesthesia, Intensive Care and Pain Medicine, Sant'Andrea University Hospital, Rome, Italy
| | - Sanzio Candeletti
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Irnerio 48, Bologna, 40126, Italy
| | - Patrizia Romualdi
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Irnerio 48, Bologna, 40126, Italy.
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7
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Dwivedi AR, Jaiswal S, Kukkar D, Kumar R, Singh TG, Singh MP, Gaidhane AM, Lakhanpal S, Prasad KN, Kumar B. A decade of pyridine-containing heterocycles in US FDA approved drugs: a medicinal chemistry-based analysis. RSC Med Chem 2024; 16:d4md00632a. [PMID: 39493227 PMCID: PMC11528346 DOI: 10.1039/d4md00632a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 10/10/2024] [Indexed: 11/05/2024] Open
Abstract
Heterocyclic scaffolds, particularly, pyridine-containing azaheterocycles, constitute a major part of the drugs approved in the past decade. In the present review, we explored the pyridine ring part of US FDA-approved small molecules (2014-2023). The analysis of the approved drugs bearing a pyridine ring revealed that a total of 54 drugs were approved. Among them, the significant number comprised the anticancer category (18 drugs, 33%), followed by drugs affecting the CNS system (11 drugs, 20%), which include drugs to treat migraines, Parkinsonism disorders, chemotherapeutic-induced nausea, insomnia, and ADHD or as CNS-acting analgesics or sedatives. Next, six drugs (11%) were also approved to treat rare conditions, followed by five drugs that affect the hematopoietic system. The analysis also revealed that drug approval was granted for antibiotics, antivirals, and antifungals, including drugs for the treatment of tropical and sub-tropical diseases. Primary drug targets explored were kinases, and the major metabolizing enzyme was CYP3A4. Further analysis of formulation types revealed that 50% of the approved drugs were tablets, followed by 17% capsules and 15% injections. Elemental analysis showed that most approved drugs contained sulfur, while fluorine was noted in 32 compounds. Therefore, the present review is a concerted effort to cover drugs bearing pyridine rings approved in the last decade and provide thorough discussion and commentary on their pharmacokinetics and pharmacodynamics aspects. Furthermore, in-depth structural and elemental analyses were explored, thus providing comprehensive guidance for medicinal chemists and scientists working in allied science domains.
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Affiliation(s)
| | - Shivani Jaiswal
- Institute of Pharmaceutical Research, GLA University Mathura, 17, Km Stone, National Highway #2, Delhi-Mathura Road India
| | - Deepak Kukkar
- University Centre for Research and Development, Chandigarh University Gharuan 140413 Punjab India
| | - Roshan Kumar
- Graphic Era (Deemed to be University) Clement Town Dehradun 248002 India
- Department Of Microbiology, Central University of Punjab VPO-Ghudda Punjab-151401 India
| | - Thakur Gurjeet Singh
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University Rajpura 140401 Punjab India
| | - Mahendra Pratap Singh
- Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University Chennai India
| | - Abhay M Gaidhane
- Jawaharlal Nehru Medical College, and Global Health Academy, School of Epidemiology and Public Health, Datta Meghe Institute of Higher Education Wardha India
| | - Sorabh Lakhanpal
- Division of Research and Development, Lovely Professional University Phagwara-144411 India
| | | | - Bhupinder Kumar
- Department of Pharmaceutical Sciences, Chauras Campus, HNB Garhwal University (A Central University) Srinagar Uttarakhand 246174 India
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8
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Manning JJ, Finlay DB, Glass M. GPCR kinase subtype requirements for arrestin-2 and -3 translocation to the cannabinoid CB 1 receptor and the consequences on G protein signalling. Biochem Pharmacol 2024; 224:116190. [PMID: 38604257 DOI: 10.1016/j.bcp.2024.116190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 04/02/2024] [Accepted: 04/04/2024] [Indexed: 04/13/2024]
Abstract
Arrestins are key negative regulators of G Protein-Coupled Receptors (GPCRs) through mediation of G protein desensitisation and receptor internalisation. Arrestins can also contribute to signal transduction by scaffolding downstream signalling effectors for activation. GPCR kinase (GRK) enzymes phosphorylate the intracellular C-terminal domain, or intracellular loop regions of GPCRs to promote arrestin interaction. There are seven different GRK subtypes, which may uniquely phosphorylate the C-terminal tail in a type of 'phosphorylation barcode,' potentially differentially contributing to arrestin translocation and arrestin-dependent signalling. Such contributions may be exploited to develop arrestin-biased ligands. Here, we examine the effect of different GRK subtypes on the ability to promote translocation of arrestin-2 and arrestin-3 to the cannabinoid CB1 receptor (CB1) with a range of ligands. We find that most GRK subtypes (including visual GRK1) can enhance arrestin-2 and -3 translocation to CB1, and that GRK-dependent changes in arrestin-2 and arrestin-3 translocation were broadly shared for most agonists tested. GRK2/3 generally enhanced arrestin translocation more than the other GRK subtypes, with some small differences between ligands. We also explore the interplay between G protein activity and GRK2/3-dependent arrestin translocation, highlighting that high-efficacy G protein agonists will cause GRK2/3 dependent arrestin translocation. This study supports the hypothesis that arrestin-biased ligands for CB1 must engage GRK5/6 rather than GRK2/3, and G protein-biased ligands must have inherently low efficacy.
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Affiliation(s)
- Jamie J Manning
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - David B Finlay
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Michelle Glass
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
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9
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Wegert A, Monnee M, de Graaf W, van Holst F, Bolcato G, Díaz JL, Dordal A, Portillo-Salido E, Reinoso RF, Yeste S, Torrens A, Almansa C. Towards Multitargeted Ligands as Pain Therapeutics: Dual Ligands of the Ca vα2δ-1 Subunit of Voltage-Gated Calcium Channel and the μ-Opioid Receptor. ChemMedChem 2024; 19:e202300473. [PMID: 38230842 DOI: 10.1002/cmdc.202300473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 12/05/2023] [Indexed: 01/18/2024]
Abstract
The synthesis and pharmacological activity of a new series of dual ligands combining activities towards the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the μ-opioid receptor (MOR) as novel pain therapeutics are reported. A careful exploration of the pharmacophores related to both targets, which in principle had few common characteristics, led to the design of novel compounds exhibiting both activities. The construction of the dual ligands started from published Cavα2δ-1 ligands, onto which MOR ligand pharmacophoric elements were added. This exercise led to new amino-acidic substances with good affinities on both targets as well as good metabolic and physicochemical profiles and low potential for drug-drug interactions. A representative compound, (2S,4S)-4-(4-chloro-3-(((cis)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid, displayed promising analgesic activities in several in vivo pain models as well as a reduced side-effect profile in relation to morphine.
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Affiliation(s)
- Anita Wegert
- Symeres, Kerkenbos 1013, 6546 BB, Nijmegen, The, Netherlands
| | - Menno Monnee
- Symeres, Kerkenbos 1013, 6546 BB, Nijmegen, The, Netherlands
| | - Wouter de Graaf
- Symeres, Kerkenbos 1013, 6546 BB, Nijmegen, The, Netherlands
| | - Frank van Holst
- Symeres, Kerkenbos 1013, 6546 BB, Nijmegen, The, Netherlands
| | | | - José Luis Díaz
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028, Barcelona, Spain
| | - Albert Dordal
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028, Barcelona, Spain
| | | | - Raquel F Reinoso
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028, Barcelona, Spain
| | - Sandra Yeste
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028, Barcelona, Spain
| | - Antoni Torrens
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028, Barcelona, Spain
| | - Carmen Almansa
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028, Barcelona, Spain
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10
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Babcock DJ, Wolfram AJ, Barney JL, Servagno SM, Sharma A, Nacsa ED. A free-radical design featuring an intramolecular migration for a synthetically versatile alkyl-(hetero)arylation of simple olefins. Chem Sci 2024; 15:4031-4040. [PMID: 38487219 PMCID: PMC10935719 DOI: 10.1039/d3sc06476j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/02/2024] [Indexed: 03/17/2024] Open
Abstract
A free-radical approach has enabled the development of a synthetically versatile alkyl-(hetero)arylation of olefins. Alkyl and (hetero)aryl groups were added concurrently to a full suite of mono- to tetrasubstituted simple alkenes (i.e., without requiring directing or electronically activating groups) for the first time. Key advances also included the introduction of synthetically diversifiable alkyl groups featuring different degrees of substitution, good diastereocontrol in both cyclic and acyclic settings, the addition of biologically valuable heteroarenes featuring Lewis basic nitrogen atoms as well as simple benzenes, and the generation of either tertiary or quaternary benzylic centers. The synthetic potential of this transformation was demonstrated by leveraging it as the key step in a concise synthesis of oliceridine, a new painkiller that received FDA approval in 2020.
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Affiliation(s)
- Dylan J Babcock
- The Pennsylvania State University, Department of Chemistry University Park PA 16802 USA
| | - Andrew J Wolfram
- The Pennsylvania State University, Department of Chemistry University Park PA 16802 USA
| | - Jaxon L Barney
- The Pennsylvania State University, Department of Chemistry University Park PA 16802 USA
| | - Santino M Servagno
- The Pennsylvania State University, Department of Chemistry University Park PA 16802 USA
| | - Ayush Sharma
- The Pennsylvania State University, Department of Chemistry University Park PA 16802 USA
| | - Eric D Nacsa
- The Pennsylvania State University, Department of Chemistry University Park PA 16802 USA
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11
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Nürnberg B, Beer-Hammer S, Reisinger E, Leiss V. Non-canonical G protein signaling. Pharmacol Ther 2024; 255:108589. [PMID: 38295906 DOI: 10.1016/j.pharmthera.2024.108589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 12/18/2023] [Accepted: 01/08/2024] [Indexed: 02/17/2024]
Abstract
The original paradigm of classical - also referred to as canonical - cellular signal transduction of heterotrimeric G proteins (G protein) is defined by a hierarchical, orthograde interaction of three players: the agonist-activated G protein-coupled receptor (GPCR), which activates the transducing G protein, that in turn regulates its intracellular effectors. This receptor-transducer-effector concept was extended by the identification of regulators and adapters such as the regulators of G protein signaling (RGS), receptor kinases like βARK, or GPCR-interacting arrestin adapters that are integrated into this canonical signaling process at different levels to enable fine-tuning. Finally, the identification of atypical signaling mechanisms of classical regulators, together with the discovery of novel modulators, added a new and fascinating dimension to the cellular G protein signal transduction. This heterogeneous group of accessory G protein modulators was coined "activators of G protein signaling" (AGS) proteins and plays distinct roles in canonical and non-canonical G protein signaling pathways. AGS proteins contribute to the control of essential cellular functions such as cell development and division, intracellular transport processes, secretion, autophagy or cell movements. As such, they are involved in numerous biological processes that are crucial for diseases, like diabetes mellitus, cancer, and stroke, which represent major health burdens. Although the identification of a large number of non-canonical G protein signaling pathways has broadened the spectrum of this cellular communication system, their underlying mechanisms, functions, and biological effects are poorly understood. In this review, we highlight and discuss atypical G protein-dependent signaling mechanisms with a focus on inhibitory G proteins (Gi) involved in canonical and non-canonical signal transduction, review recent developments and open questions, address the potential of new approaches for targeted pharmacological interventions.
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Affiliation(s)
- Bernd Nürnberg
- Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomics, and ICePhA Mouse Clinic, University of Tübingen, Wilhelmstraße 56, D-72074 Tübingen, Germany.
| | - Sandra Beer-Hammer
- Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomics, and ICePhA Mouse Clinic, University of Tübingen, Wilhelmstraße 56, D-72074 Tübingen, Germany
| | - Ellen Reisinger
- Gene Therapy for Hearing Impairment Group, Department of Otolaryngology - Head & Neck Surgery, University of Tübingen Medical Center, Elfriede-Aulhorn-Straße 5, D-72076 Tübingen, Germany
| | - Veronika Leiss
- Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomics, and ICePhA Mouse Clinic, University of Tübingen, Wilhelmstraße 56, D-72074 Tübingen, Germany
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12
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Ni Y, Gao H, Ouyang W, Yang G, Cheng M, Ding L. Pharmacokinetics, metabolite profiling, safety and tolerability of YZJ-4729 tartrate, a novel G protein-biased μ-opioid receptor agonist, in healthy Chinese subjects. Front Pharmacol 2024; 14:1295319. [PMID: 38264529 PMCID: PMC10803517 DOI: 10.3389/fphar.2023.1295319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 12/26/2023] [Indexed: 01/25/2024] Open
Abstract
Objective: YZJ-4729 is a novel G protein-biased μ-opioid receptor agonist for the treatment of acute pain in adult patients who require intravenous opioid analgesic therapy. The aim of this study was to assess the pharmacokinetics, metabolite profiling, safety and tolerability of YZJ-4729 in healthy Chinese subjects following the single intravenous doses ranged from 0.2 mg to 6 mg. Methods: This single-center, randomized, double-blind, placebo-controlled clinical study was conducted in 54 healthy male and female Chinese subjects after single ascending doses of YZJ-4729 tartrate (0.2, 0.5, 1.5, 3, 4.5, and 6 mg). Subjects in each cohort were assigned randomly to receive a single intravenous dose of YZJ-4729 tartrate injection or placebo at a ratio of 4:1. Pharmacokinetic characteristics, metabolite profiling, safety and tolerability profiles of the study drug were evaluated. Results: Overall, YZJ-4729 was safe and well tolerated in healthy Chinese subjects. The study drug reached peak plasma concentrations nearly at the end of the infusion. After administration, YZJ-4729 was eliminated rapidly with a terminal elimination half-life of 0.862-2.50 h, and excreted little in human excreta. The maximum drug concentration and area under the plasma concentration-time curve increased with dose escalation across the entire dose range. YZJ-4729 experienced extensive metabolism in human body. A total of 19 metabolites were identified and the characteristic metabolic pathways involved hydroxylation, ketone formation, N-dealkylation and glucuronide conjugation. Metabolite M10 was the most abundant circulating metabolite, and represented over 10% of total drug-related systemic exposure. Further PK and safety evaluation of M10 was necessary. Conclusion: The clinical study results laid a foundation for the further clinical studies of YZJ-4729 in patients. Clinical Trial Registration: http://www.chinadrugtrials.org.cn, identifier CTR20222574.
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Affiliation(s)
- Yufeng Ni
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
- Yangtze River Pharmaceutical Group Co, Ltd., Taizhou, China
| | - Huaye Gao
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
- Nanjing Jiening Pharmaceutical Technology Co, Ltd., Nanjing, China
| | - Wen Ouyang
- Department of Anesthesiology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Guoping Yang
- Clinical Trial Research Center, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Minlu Cheng
- Nanjing Jiening Pharmaceutical Technology Co, Ltd., Nanjing, China
- Nanjing Clinical Tech. Laboratories Inc., Nanjing, China
| | - Li Ding
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China
- Nanjing Jiening Pharmaceutical Technology Co, Ltd., Nanjing, China
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13
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Zhu C, Lan X, Wei Z, Yu J, Zhang J. Allosteric modulation of G protein-coupled receptors as a novel therapeutic strategy in neuropathic pain. Acta Pharm Sin B 2024; 14:67-86. [PMID: 38239234 PMCID: PMC10792987 DOI: 10.1016/j.apsb.2023.07.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/09/2023] [Accepted: 07/12/2023] [Indexed: 01/22/2024] Open
Abstract
Neuropathic pain is a debilitating pathological condition that presents significant therapeutic challenges in clinical practice. Unfortunately, current pharmacological treatments for neuropathic pain lack clinical efficacy and often lead to harmful adverse reactions. As G protein-coupled receptors (GPCRs) are widely distributed throughout the body, including the pain transmission pathway and descending inhibition pathway, the development of novel neuropathic pain treatments based on GPCRs allosteric modulation theory is gaining momentum. Extensive research has shown that allosteric modulators targeting GPCRs on the pain pathway can effectively alleviate symptoms of neuropathic pain while reducing or eliminating adverse effects. This review aims to provide a comprehensive summary of the progress made in GPCRs allosteric modulators in the treatment of neuropathic pain, and discuss the potential benefits and adverse factors of this treatment. We will also concentrate on the development of biased agonists of GPCRs, and based on important examples of biased agonist development in recent years, we will describe universal strategies for designing structure-based biased agonists. It is foreseeable that, with the continuous improvement of GPCRs allosteric modulation and biased agonist theory, effective GPCRs allosteric drugs will eventually be available for the treatment of neuropathic pain with acceptable safety.
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Affiliation(s)
- Chunhao Zhu
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
- School of Basic Medical Science, Ningxia Medical University, Yinchuan 750004, China
| | - Xiaobing Lan
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
| | - Zhiqiang Wei
- Medicinal Chemistry and Bioinformatics Center, Ocean University of China, Qingdao 266100, China
| | - Jianqiang Yu
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
| | - Jian Zhang
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
- Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China
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14
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Rodriguez P, Laskowski LJ, Pallais JP, Bock HA, Cavalco NG, Anderson EI, Calkins MM, Razzoli M, Sham YY, McCorvy JD, Bartolomucci A. Functional profiling of the G protein-coupled receptor C3aR1 reveals ligand-mediated biased agonism. J Biol Chem 2024; 300:105549. [PMID: 38072064 PMCID: PMC10796979 DOI: 10.1016/j.jbc.2023.105549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 11/21/2023] [Accepted: 12/02/2023] [Indexed: 12/29/2023] Open
Abstract
G protein-coupled receptors (GPCRs) are leading druggable targets for several medicines, but many GPCRs are still untapped for their therapeutic potential due to poor understanding of specific signaling properties. The complement C3a receptor 1 (C3aR1) has been extensively studied for its physiological role in C3a-mediated anaphylaxis/inflammation, and in TLQP-21-mediated lipolysis, but direct evidence for the functional relevance of the C3a and TLQP-21 ligands and signal transduction mechanisms are still limited. In addition, C3aR1 G protein coupling specificity is still unclear, and whether endogenous ligands, or drug-like compounds, show ligand-mediated biased agonism is unknown. Here, we demonstrate that C3aR1 couples preferentially to Gi/o/z proteins and can recruit β-arrestins to cause internalization. Furthermore, we showed that in comparison to C3a63-77, TLQP-21 exhibits a preference toward Gi/o-mediated signaling compared to β-arrestin recruitment and internalization. We also show that the purported antagonist SB290157 is a very potent C3aR1 agonist, where antagonism of ligand-stimulated C3aR1 calcium flux is caused by potent β-arrestin-mediated internalization. Finally, ligand-mediated signaling bias impacted cell function as demonstrated by the regulation of calcium influx, lipolysis in adipocytes, phagocytosis in microglia, and degranulation in mast cells. Overall, we characterize C3aR1 as a Gi/o/z-coupled receptor and demonstrate the functional relevance of ligand-mediated signaling bias in key cellular models. Due to C3aR1 and its endogenous ligands being implicated in inflammatory and metabolic diseases, these results are of relevance toward future C3aR1 drug discovery.
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Affiliation(s)
- Pedro Rodriguez
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Lauren J Laskowski
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Jean Pierre Pallais
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Hailey A Bock
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Natalie G Cavalco
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Emilie I Anderson
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Maggie M Calkins
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Maria Razzoli
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Yuk Y Sham
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - John D McCorvy
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
| | - Alessandro Bartolomucci
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA.
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15
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Moshnenko N, Kazantsev A, Chupakhin E, Bakulina O, Dar'in D. Synthetic Routes to Approved Drugs Containing a Spirocycle. Molecules 2023; 28:molecules28104209. [PMID: 37241950 DOI: 10.3390/molecules28104209] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
The use of spirocycles in drug discovery and medicinal chemistry has been booming in the last two decades. This has clearly translated into the landscape of approved drugs. Among two dozen clinically used medicines containing a spirocycle, 50% have been approved in the 21st century. The present review focuses on the notable synthetic routes to such drugs invented in industry and academia, and is intended to serve as a useful reference source of synthetic as well as general drug information for researchers engaging in the design of new spirocyclic scaffolds for medicinal use or embarking upon analog syntheses inspired by the existing approved drugs.
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Affiliation(s)
- Nazar Moshnenko
- Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
| | - Alexander Kazantsev
- Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
| | - Evgeny Chupakhin
- Institute of Living Systems, Immanuel Kant Baltic Federal University, 236016 Kaliningrad, Russia
| | - Olga Bakulina
- Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
| | - Dmitry Dar'in
- Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
- Saint Petersburg Research Institute of Phthisiopulmonology, 191036 Saint Petersburg, Russia
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16
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Asymmetric Synthesis of US-FDA Approved Drugs over Five Years (2016–2020): A Recapitulation of Chirality. Pharmaceuticals (Basel) 2023; 16:ph16030339. [PMID: 36986439 PMCID: PMC10052577 DOI: 10.3390/ph16030339] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 02/09/2023] [Accepted: 02/17/2023] [Indexed: 02/25/2023] Open
Abstract
Chirality is a major theme in the design, discovery, and development of new drugs. Historically, pharmaceuticals have been synthesized as racemic mixtures. However, the enantiomeric forms of drug molecules have distinct biological properties. One enantiomer may be responsible for the desired therapeutic effect (eutomer), whereas the other may be inactive, interfere with the therapeutic form, or exhibit toxicity (distomer). Classical chemical synthesis usually leads to a racemic mixture unless stereospecific synthesis is employed. To meet the requirements of single-enantiomeric drugs, asymmetric synthesis has evolved at the forefront of drug discovery. Asymmetric synthesis involves the conversion of an achiral starting material into a chiral product. This review emphasizes the methods used for synthesizing FDA-approved chiral drugs during 2016–2020, with a special focus on asymmetric synthesis by means of chiral induction, resolution, or chiral pool.
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17
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Hartrick CT. Exploiting Injury-Induced Peripheral Opioid Receptor Changes in Novel Analgesic Development for Chronic Pain. FRONTIERS IN PAIN RESEARCH 2022; 3:883164. [PMID: 35557854 PMCID: PMC9090307 DOI: 10.3389/fpain.2022.883164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/06/2022] [Indexed: 11/13/2022] Open
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18
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Mao Q, Zhang B, Tian S, Qin W, Chen J, Huang XP, Xin Y, Yang H, Zhen XC, Shui W, Ye N. Structural optimizations and bioevaluation of N-H aporphine analogues as Gq-biased and selective serotonin 5-HT2C receptor agonists. Bioorg Chem 2022; 123:105795. [DOI: 10.1016/j.bioorg.2022.105795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 03/31/2022] [Accepted: 04/05/2022] [Indexed: 11/29/2022]
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19
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BRET-Based Biosensors to Measure Agonist Efficacies in Histamine H 1 Receptor-Mediated G Protein Activation, Signaling and Interactions with GRKs and β-Arrestins. Int J Mol Sci 2022; 23:ijms23063184. [PMID: 35328605 PMCID: PMC8953162 DOI: 10.3390/ijms23063184] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 02/04/2023] Open
Abstract
The histamine H1 receptor (H1R) is a G protein-coupled receptor (GPCR) and plays a key role in allergic reactions upon activation by histamine which is locally released from mast cells and basophils. Consequently, H1R is a well-established therapeutic target for antihistamines that relieve allergy symptoms. H1R signals via heterotrimeric Gq proteins and is phosphorylated by GPCR kinase (GRK) subtypes 2, 5, and 6, consequently facilitating the subsequent recruitment of β-arrestin1 and/or 2. Stimulation of a GPCR with structurally different agonists can result in preferential engagement of one or more of these intracellular signaling molecules. To evaluate this so-called biased agonism for H1R, bioluminescence resonance energy transfer (BRET)-based biosensors were applied to measure H1R signaling through heterotrimeric Gq proteins, second messengers (inositol 1,4,5-triphosphate and Ca2+), and receptor-protein interactions (GRKs and β-arrestins) in response to histamine, 2-phenylhistamines, and histaprodifens in a similar cellular background. Although differences in efficacy were observed for these agonists between some functional readouts as compared to reference agonist histamine, subsequent data analysis using an operational model of agonism revealed only signaling bias of the agonist Br-phHA-HA in recruiting β-arrestin2 to H1R over Gq biosensor activation.
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20
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Singh R, Zogg H, Ghoshal UC, Ro S. Current Treatment Options and Therapeutic Insights for Gastrointestinal Dysmotility and Functional Gastrointestinal Disorders. Front Pharmacol 2022; 13:808195. [PMID: 35145413 PMCID: PMC8822166 DOI: 10.3389/fphar.2022.808195] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
Functional gastrointestinal disorders (FGIDs) have been re-named as disorders of gut-brain interactions. These conditions are not only common in clinical practice, but also in the community. In reference to the Rome IV criteria, the most common FGIDs, include functional dyspepsia (FD) and irritable bowel syndrome (IBS). Additionally, there is substantial overlap of these disorders and other specific gastrointestinal motility disorders, such as gastroparesis. These disorders are heterogeneous and are intertwined with several proposed pathophysiological mechanisms, such as altered gut motility, intestinal barrier dysfunction, gut immune dysfunction, visceral hypersensitivity, altered GI secretion, presence and degree of bile acid malabsorption, microbial dysbiosis, and alterations to the gut-brain axis. The treatment options currently available include lifestyle modifications, dietary and gut microbiota manipulation interventions including fecal microbiota transplantation, prokinetics, antispasmodics, laxatives, and centrally and peripherally acting neuromodulators. However, treatment that targets the pathophysiological mechanisms underlying the symptoms are scanty. Pharmacological agents that are developed based on the cellular and molecular mechanisms underlying pathologies of these disorders might provide the best avenue for future pharmaceutical development. The currently available therapies lack long-term effectiveness and safety for their use to treat motility disorders and FGIDs. Furthermore, the fundamental challenges in treating these disorders should be defined; for instance, 1. Cause and effect cannot be disentangled between symptoms and pathophysiological mechanisms due to current therapies that entail the off-label use of medications to treat symptoms. 2. Despite the knowledge that the microbiota in our gut plays an essential part in maintaining gut health, their exact functions in gut homeostasis are still unclear. What constitutes a healthy microbiome and further, the precise definition of gut microbial dysbiosis is lacking. More comprehensive, large-scale, and longitudinal studies utilizing multi-omics data are needed to dissect the exact contribution of gut microbial alterations in disease pathogenesis. Accordingly, we review the current treatment options, clinical insight on pathophysiology, therapeutic modalities, current challenges, and therapeutic clues for the clinical care and management of functional dyspepsia, gastroparesis, irritable bowel syndrome, functional constipation, and functional diarrhea.
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Affiliation(s)
- Rajan Singh
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, United States
| | - Hannah Zogg
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, United States
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Seungil Ro
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, United States
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21
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Opioid Receptors and Protonation-Coupled Binding of Opioid Drugs. Int J Mol Sci 2021; 22:ijms222413353. [PMID: 34948150 PMCID: PMC8707250 DOI: 10.3390/ijms222413353] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/09/2021] [Accepted: 12/09/2021] [Indexed: 01/01/2023] Open
Abstract
Opioid receptors are G-protein-coupled receptors (GPCRs) part of cell signaling paths of direct interest to treat pain. Pain may associate with inflamed tissue characterized by acidic pH. The potentially low pH at tissue targeted by opioid drugs in pain management could impact drug binding to the opioid receptor, because opioid drugs typically have a protonated amino group that contributes to receptor binding, and the functioning of GPCRs may involve protonation change. In this review, we discuss the relationship between structure, function, and dynamics of opioid receptors from the perspective of the usefulness of computational studies to evaluate protonation-coupled opioid-receptor interactions.
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22
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Finlay JE, Leslie K. Sedation/analgesia techniques for nonoperating room anesthesia: new drugs and devices. Curr Opin Anaesthesiol 2021; 34:678-682. [PMID: 34419992 DOI: 10.1097/aco.0000000000001057] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW The purpose of this article is to review new drugs and devices for nonoperating room anesthesia (NORA). RECENT FINDINGS Remimazolam is an ultra-short-acting, water-soluble intravenous benzodiazepine with a fast onset and offset that has been approved recently for use in procedural sedation. Phase III trials have established the effectiveness of remimazolam sedation compared with placebo and midazolam in gastrointestinal endoscopy and bronchoscopy. More research is required investigating remimazolam in real-world NORA settings, including comparisons with propofol sedation. Oliceridine is a μ-agonist with selectivity for the G protein pathway and low potency for β-arrestin recruitment. As such it may be associated with less nausea, vomiting and respiratory depression than traditional opioids used. Although no studies have been published about oliceridine use in NORA to date, results from surgical studies indicate a potential place in nonoperating room practice. Research continues into alternative methods of drug delivery, such as patient-controlled sedation but no new devices are described. SUMMARY Further studies are required before these new drugs and devices are embraced in NORA.
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Affiliation(s)
- Janna E Finlay
- Department of Anaesthesia and Pain Management, Royal Melbourne Hospital
| | - Kate Leslie
- Department of Anaesthesia and Pain Management, Royal Melbourne Hospital
- Department of Critical Care, Melbourne Medical School, University of Melbourne, Melbourne, Australia
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23
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Giannos T, Lešnik S, Bren U, Hodošček M, Domratcheva T, Bondar AN. CHARMM Force-Field Parameters for Morphine, Heroin, and Oliceridine, and Conformational Dynamics of Opioid Drugs. J Chem Inf Model 2021; 61:3964-3977. [PMID: 34351148 DOI: 10.1021/acs.jcim.1c00667] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Opioid drug binding to specialized G protein-coupled receptors (GPCRs) can lead to analgesia upon activation via downstream Gi protein signaling and to severe side effects via activation of the β-arrestin signaling pathway. Knowledge of how different opioid drugs interact with receptors is essential, as it can inform and guide the design of safer therapeutics. We performed quantum and classical mechanical computations to explore the potential energy landscape of four opioid drugs: morphine and its derivatives heroin and fentanyl and for the unrelated oliceridine. From potential energy profiles for bond twists and from interactions between opioids and water, we derived a set of force-field parameters that allow a good description of structural properties and intermolecular interactions of the opioids. Potential of mean force profiles computed from molecular dynamics simulations indicate that fentanyl and oliceridine have complex energy landscapes with relatively small energy penalties, suggesting that interactions with the receptor could select different binding poses of the drugs.
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Affiliation(s)
- Thomas Giannos
- Theoretical Molecular Biophysics Group, Department of Physics, Freie Universität Berlin, Arnimallee 14, D-14195 Berlin, Germany
| | - Samo Lešnik
- Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova 17, SI-2000 Maribor, Slovenia
| | - Urban Bren
- Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova 17, SI-2000 Maribor, Slovenia.,Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, SI-6000 Koper, Slovenia
| | - Milan Hodošček
- Theory Department, National Institute of Chemistry Slovenia, Hajdrihova 19, SI-1001 Ljubljana, Slovenia
| | - Tatiana Domratcheva
- Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia.,Department of Biomolecular Mechanisms, Max-Planck-Institut fur Medizinische Forschung, Jahnstrasse 29, D-69120 Heidelberg, Germany
| | - Ana-Nicoleta Bondar
- Theoretical Molecular Biophysics Group, Department of Physics, Freie Universität Berlin, Arnimallee 14, D-14195 Berlin, Germany.,Faculty of Physics, University of Bucharest, Atomiştilor 405, Măgurele 077125, Romania.,Institute for Neuroscience and Medicine and Institute for Advanced Simulations (IAS-5/INM-9), Computational Biomedicine, Forschungszentrum Jülich, 52425 Jülich, Germany
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24
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Manning JJ, Green HM, Glass M, Finlay DB. Pharmacological selection of cannabinoid receptor effectors: Signalling, allosteric modulation and bias. Neuropharmacology 2021; 193:108611. [PMID: 34000272 DOI: 10.1016/j.neuropharm.2021.108611] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/26/2021] [Accepted: 05/10/2021] [Indexed: 12/14/2022]
Abstract
The type-1 cannabinoid receptor (CB1) is a promising drug target for a wide range of diseases. However, many existing and novel candidate ligands for CB1 have shown only limited therapeutic potential. Indeed, no ligands are currently approved for the clinic except formulations of the phytocannabinoids Δ9-THC and CBD and a small number of analogues. A key limitation of many promising CB1 ligands are their on-target adverse effects, notably including psychoactivity (agonists) and depression/suicidal ideation (inverse agonists). Recent drug development attempts have therefore focussed on altering CB1 signalling profiles in two ways. Firstly, with compounds that enhance or reduce the signalling of endogenous (endo-) cannabinoids, namely allosteric modulators. Secondly, with compounds that probe the capability of selectively targeting specific cellular signalling pathways that may mediate therapeutic effects using biased ligands. This review will summarise the current paradigm of CB1 signalling in terms of the intracellular transduction pathways acted on by the receptor. The development of compounds that selectively activate CB1 signalling pathways, whether allosterically or via orthosteric agonist bias, will also be addressed.
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Affiliation(s)
- Jamie J Manning
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand, PO Box 56, Dunedin, 9054, New Zealand
| | - Hayley M Green
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand, PO Box 56, Dunedin, 9054, New Zealand
| | - Michelle Glass
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand, PO Box 56, Dunedin, 9054, New Zealand
| | - David B Finlay
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand, PO Box 56, Dunedin, 9054, New Zealand.
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Obeng S, Hiranita T, León F, McMahon LR, McCurdy CR. Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery. J Med Chem 2021; 64:6523-6548. [PMID: 33956427 DOI: 10.1021/acs.jmedchem.1c00028] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Because of the problems associated with opioids, drug discovery efforts have been employed to develop opioids with reduced side effects using approaches such as biased opioid agonism, multifunctional opioids, and allosteric modulation of opioid receptors. Receptor targets such as adrenergic, cannabinoid, P2X3 and P2X7, NMDA, serotonin, and sigma, as well as ion channels like the voltage-gated sodium channels Nav1.7 and Nav1.8 have been targeted to develop novel analgesics. Several enzymes, such as soluble epoxide hydrolase, sepiapterin reductase, and MAGL/FAAH, have also been targeted to develop novel analgesics. In this review, old and recent targets involved in pain signaling and compounds acting at these targets are summarized. In addition, strategies employed to reduce side effects, increase potency, and efficacy of opioids are also elaborated. This review should aid in propelling drug discovery efforts to discover novel analgesics.
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Affiliation(s)
- Samuel Obeng
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.,Department Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
| | - Takato Hiranita
- Department Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
| | - Francisco León
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia 29208, United States
| | - Lance R McMahon
- Department Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
| | - Christopher R McCurdy
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.,Translational Drug Development Core, Clinical and Translational Sciences Institute, University of Florida, Gainesville, Florida 32610, United States
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Sałaciak K, Pytka K. Biased agonism in drug discovery: Is there a future for biased 5-HT 1A receptor agonists in the treatment of neuropsychiatric diseases? Pharmacol Ther 2021; 227:107872. [PMID: 33905796 DOI: 10.1016/j.pharmthera.2021.107872] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/17/2021] [Accepted: 04/19/2021] [Indexed: 12/11/2022]
Abstract
Serotonin (5-HT) is one of the fundamental neurotransmitters that contribute to the information essential for an organism's normal, physiological function. Serotonin acts centrally and systemically. The 5-HT1A receptor is the most widespread serotonin receptor, and participates in many brain-related disorders, including anxiety, depression, and cognitive impairments. The 5-HT1A receptor can activate several different biochemical pathways and signals through both G protein-dependent and G protein-independent pathways. Preclinical experiments indicate that distinct signaling pathways in specific brain regions may be crucial for antidepressant-like, anxiolytic-like, and procognitive responses. Therefore, the development of new ligands that selectively target a particular signaling pathway(s) could open new possibilities for more effective and safer pharmacotherapy. This review discusses the current state of preclinical studies focusing on the concept of functional selectivity (biased agonism) regarding the 5-HT1A receptor and its role in antidepressant-like, anxiolytic-like, and procognitive regulation. Such work highlights not only the differential effects of targeted autoreceptors, vs. heteroreceptors, but also the importance of targeting specific downstream intracellular signaling processes, thereby enhancing favorable over unfavorable signaling activation.
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Affiliation(s)
- Kinga Sałaciak
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland
| | - Karolina Pytka
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
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27
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Kayki-Mutlu G, Michel MC. A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2020. Naunyn Schmiedebergs Arch Pharmacol 2021; 394:839-852. [PMID: 33864098 PMCID: PMC8051285 DOI: 10.1007/s00210-021-02085-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 03/31/2021] [Indexed: 01/03/2023]
Abstract
While the COVID-19 pandemic also affected the work of regulatory authorities, the US Food and Drug Administration approved a total of 53 new drugs in 2020, one of the highest numbers in the past decades. Most newly approved drugs related to oncology (34%) and neurology (15%). We discuss these new drugs by level of innovation they provide, i.e., first to treat a condition, first using a novel mechanisms of action, and "others." Six drugs were first in indication, 15 first using a novel mechanism of action, and 32 other. This includes many drugs for the treatment of orphan indications and some for the treatment of tropical diseases previously neglected for commercial reasons. Small molecules continue to dominate new drug approvals, followed by antibodies. Of note, newly approved drugs also included small-interfering RNAs and antisense oligonucleotides. These data show that the trend for declines in drug discovery and development has clearly been broken.
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Affiliation(s)
- Gizem Kayki-Mutlu
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara, Turkey
| | - Martin C Michel
- Department of Pharmacology, Johannes Gutenberg University, Langenbeckstr. 1, 55118, Mainz, Germany.
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28
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Jiang Y, Yan M, Wang C, Wang Q, Chen X, Zhang R, Wan L, Ji B, Dong B, Wang H, Chen J. The Effects of Apelin and Elabela Ligands on Apelin Receptor Distinct Signaling Profiles. Front Pharmacol 2021; 12:630548. [PMID: 33746758 PMCID: PMC7970304 DOI: 10.3389/fphar.2021.630548] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/27/2021] [Indexed: 12/13/2022] Open
Abstract
Apelin and Elabela are endogenous peptide ligands for Apelin receptor (APJ), a widely expressed G protein-coupled receptor. They constitute a spatiotemporal dual ligand system to control APJ signal transduction and function. We investigated the effects of Apelin-13, pGlu1-apelin-13, Apelin-17, Apelin-36, Elabela-21 and Elabela-32 peptides on APJ signal transduction. Whether different ligands are biased to different APJ mediated signal transduction pathways was studied. We observed the different changes of G protein dependent and β-arrestin dependent signaling pathways after APJ was activated by six peptide ligands. We demonstrated that stimulation with APJ ligands resulted in dose-dependent increases in both G protein dependent [cyclic AMP (cAMP), Ca2+ mobilization, and the early phase extracellular related kinase (ERK) activation] and β-arrestin dependent [GRKs, β-arrestin 1, β-arrestin 2, and β2 subunit of the clathrin adaptor AP2] signaling pathways. However, the ligands exhibited distinct signaling profiles. Elabela-32 showed a >1000-fold bias to the β-statin-dependent signaling pathway. These data provide that Apelin-17 was biased toward β-arrestin dependent signaling. Eabela-21 and pGlu1-Apelin-13 exhibited very distinct activities on the G protein dependent pathway. The activity profiles of these ligands could be valuable for the development of drugs with high selectivity for specific APJ downstream signaling pathways.
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Affiliation(s)
- Yunlu Jiang
- Neurobiology Key Laboratory of Jining Medical University in Colleges of Shandong, Jining Medical University, Jining, China
| | - Maocai Yan
- School of Pharmacy, Jining Medical University, Shandong, China
| | - Chunmei Wang
- Neurobiology Key Laboratory of Jining Medical University in Colleges of Shandong, Jining Medical University, Jining, China
| | - Qinqin Wang
- Neurobiology Key Laboratory of Jining Medical University in Colleges of Shandong, Jining Medical University, Jining, China
| | - Xiaoyu Chen
- Department of Physiology, Shandong First Medical University, Shandong, China
| | - Rumin Zhang
- Neurobiology Key Laboratory of Jining Medical University in Colleges of Shandong, Jining Medical University, Jining, China
| | - Lei Wan
- Neurobiology Key Laboratory of Jining Medical University in Colleges of Shandong, Jining Medical University, Jining, China
| | - Bingyuan Ji
- Neurobiology Key Laboratory of Jining Medical University in Colleges of Shandong, Jining Medical University, Jining, China
| | - Bo Dong
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Huiyun Wang
- School of Pharmacy, Jining Medical University, Shandong, China
| | - Jing Chen
- Neurobiology Key Laboratory of Jining Medical University in Colleges of Shandong, Jining Medical University, Jining, China.,Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
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New drug approvals for 2020: Synthesis and clinical applications. Eur J Med Chem 2021; 215:113284. [PMID: 33611190 DOI: 10.1016/j.ejmech.2021.113284] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 02/03/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023]
Abstract
53 New drugs including 38 chemical entities and 15 biologics were approved by the U.S. Food and Drug Administration during 2020. Among the marketed drugs, 34 new small molecule drugs and 4 new diagnostic agents with privileged structures and novel clinical applications represent as promising leads for the development of new drugs with the similar indications and improved therapeutic efficacy. This review is mainly focused on the clinical applications and synthetic methods of 34 small-molecule drugs newly approved by the FDA in 2020.
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Abstract
Preclinical models that assess "pain" in rodents typically measure increases in behaviors produced by a "pain stimulus." A large literature exists showing that kappa opioid receptor (KOR) agonists can decrease these "pain-stimulated behaviors" following many different pain stimuli. Despite showing apparent antinociceptive properties in these preclinical models, KOR agonists failed as analgesics in clinical trials. Recent studies that assessed decreases in behavior due to a pain stimulus show that KOR agonists are not effective in restoring these "pain-depressed behaviors" to normal levels, which agrees with the lack of effectiveness for KOR agonists in clinical trials. One current explanation for the failure of previous KOR agonists in clinical trials is that those agonists activated beta-arrestin signaling and that KOR agonists with a greater bias for G protein signaling will be more successful. However, neither G protein-biased agonists nor beta-arrestin-biased agonists are very effective in assays of pain-depressed behavior, which suggests that novel biased agonists may still not be effective analgesics. This review provides a concise account of the effectiveness of KOR agonists in preclinical models of pain-stimulated and pain-depressed behaviors following the administration of different pain stimuli. Based on the previous results, it may be appropriate to include both behaviors when testing the analgesic potential of KOR agonists.
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Affiliation(s)
- Matthew F Lazenka
- Department of Biology and Chemistry, Liberty University, Lynchburg, VA, USA.
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Abstract
Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compounds has given rise to the development of synthetic methodologies for the preparation of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to obtain spirocyclic systems. The impact of spirocycles on potency and selectivity, including the aspect of stereochemistry, is discussed. Furthermore, we examine the changes in physicochemical properties as well as in in vitro and in vivo ADME using selected studies that compare spirocyclic compounds to their nonspirocyclic counterparts. In conclusion, the value of spirocyclic scaffolds in medicinal chemistry is discussed.
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Affiliation(s)
- Kerstin Hiesinger
- Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue Straße 9, D-60348 Frankfurt am Main, Germany
| | - Dmitry Dar'in
- Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
| | - Ewgenij Proschak
- Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue Straße 9, D-60348 Frankfurt am Main, Germany
| | - Mikhail Krasavin
- Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
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