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Borah MP, Trakroo D, Soni N, Kumari P, Baidya M. Exploring Bias in GPCR Signaling and its Implication in Drug Development: A One-Sided Affair. Biochemistry 2025; 64:1-14. [PMID: 39613476 DOI: 10.1021/acs.biochem.4c00676] [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] [Indexed: 12/01/2024]
Abstract
G protein-coupled receptors (GPCRs) play a pivotal role in regulating numerous physiological processes through their interactions with two key effectors: G proteins and β-arrestins (βarrs). This makes them crucial targets for therapeutic drug development. Interestingly, the evolving concept of biased signaling where ligands selectively activate either the G proteins or the βarrs has not only refined our understanding of segregation of physiological responses downstream of GPCRs but has also revolutionized drug discovery, offering the potential for treatments with enhanced efficacy and minimal side effects. This Review explores the mechanisms behind biased agonism, exploring it through various lenses, including ligand, receptor, cellular systems, location, and tissue-specific biases. It also offers structural insights into both orthosteric and allosteric ligand-binding pockets, structural rearrangements associated with the loops, and how ligand-engineering can contribute to biased signaling. Moreover, we also discuss the unique conformational signature in an intrinsically biased GPCR, which currently remains relatively less explored and adds a new dimension in biased signaling. Lastly, we address the translational challenges and practical considerations in characterizing bias, emphasizing its therapeutic potential and the latest advancements in drug development. By designing ligands that target specific signaling pathways, biased signaling presents a transformative approach to creating safer and more effective therapies. This Review focuses on our current understanding of GPCR-biased signaling, discussing potential mechanisms that lead to bias, the effect of bias on GPCR structures at a molecular level, recent advancements, and its profound potential to drive innovation in drug discovery.
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Affiliation(s)
- Madhurjya Protim Borah
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jammu, Jammu, Jammu and Kashmir 181221, India
| | - Deepika Trakroo
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jammu, Jammu, Jammu and Kashmir 181221, India
| | - Neeraj Soni
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jammu, Jammu, Jammu and Kashmir 181221, India
| | - Punita Kumari
- Indian Institute of Science Education and Research Bhopal (IISERB), Department of Biological Sciences, Bhopal, Madhya Pradesh 462066, India
| | - Mithu Baidya
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jammu, Jammu, Jammu and Kashmir 181221, India
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Nezamuldeen L, Jafri MS. Boolean Modeling of Biological Network Applied to Protein-Protein Interaction Network of Autism Patients. BIOLOGY 2024; 13:606. [PMID: 39194544 DOI: 10.3390/biology13080606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/01/2024] [Accepted: 08/06/2024] [Indexed: 08/29/2024]
Abstract
Cellular molecules interact with one another in a structured manner, defining a regulatory network topology that describes cellular mechanisms. Genetic mutations alter these networks' pathways, generating complex disorders such as autism spectrum disorder (ASD). Boolean models have assisted in understanding biological system dynamics since Kauffman's 1969 discovery, and various analytical tools for regulatory networks have been developed. This study examined the protein-protein interaction network created in our previous publication of four ASD patients using the SPIDDOR R package, a Boolean model-based method. The aim is to examine how patients' genetic variations in INTS6L, USP9X, RSK4, FGF5, FLNA, SUMF1, and IDS affect mTOR and Wnt cell signaling convergence. The Boolean network analysis revealed abnormal activation levels of essential proteins such as β-catenin, MTORC1, RPS6, eIF4E, Cadherin, and SMAD. These proteins affect gene expression, translation, cell adhesion, shape, and migration. Patients 1 and 2 showed consistent patterns of increased β-catenin activity and decreased MTORC1, RPS6, and eIF4E activity. However, patient 2 had an independent decrease in Cadherin and SMAD activity due to the FLNA mutation. Patients 3 and 4 have an abnormal activation of the mTOR pathway, which includes the MTORC1, RPS6, and eIF4E genes. The shared mTOR pathway behavior in these patients is explained by a shared mutation in two closely related proteins (SUMF1 and IDS). Diverse activities in β-catenin, MTORC1, RPS6, eIF4E, Cadherin, and SMAD contributed to the reported phenotype in these individuals. Furthermore, it unveiled the potential therapeutic options that could be suggested to these individuals.
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Affiliation(s)
- Leena Nezamuldeen
- School of Systems Biology, George Mason University, Fairfax, VA 22030, USA
- King Fahd Medical Research Centre, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mohsin Saleet Jafri
- School of Systems Biology, George Mason University, Fairfax, VA 22030, USA
- Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Valle-León M, Casajuana-Martin N, Del Torrent CL, Argerich J, Gómez-Acero L, Sahlholm K, Ferré S, Pardo L, Ciruela F. Unique effect of clozapine on adenosine A 2A-dopamine D 2 receptor heteromerization. Biomed Pharmacother 2023; 160:114327. [PMID: 36736280 PMCID: PMC11959194 DOI: 10.1016/j.biopha.2023.114327] [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: 10/25/2022] [Revised: 01/21/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
The striatal dopamine D2 receptor (D2R) is generally accepted to be involved in positive symptoms of schizophrenia and is a main target for clinically used antipsychotics. D2R are highly expressed in the striatum, where they form heteromers with the adenosine A2A receptor (A2AR). Changes in the density of A2AR-D2R heteromers have been reported in postmortem tissue from patients with schizophrenia, but the degree to which A2R are involved in schizophrenia and the effect of antipsychotic drugs is unknown. Here, we examine the effect of exposure to three prototypical antipsychotic drugs on A2AR-D2R heteromerization in mammalian cells using a NanoBiT assay. After 16 h of exposure, a significant increase in the density of A2AR-D2R heteromers was found with haloperidol and aripiprazole, but not with clozapine. On the other hand, clozapine, but not haloperidol or aripiprazole, was associated with a significant decrease in A2AR-D2R heteromerization after 2 h of treatment. Computational binding models of these compounds revealed distinctive molecular signatures that explain their different influence on heteromerization. The bulky tricyclic moiety of clozapine displaces TM 5 of D2R, inducing a clash with A2AR, while the extended binding mode of haloperidol and aripiprazole stabilizes a specific conformation of the second extracellular loop of D2R that enhances the interaction with A2AR. It is proposed that an increase in A2AR-D2R heteromerization is involved in the extrapyramidal side effects (EPS) of antipsychotics and that the specific clozapine-mediated destabilization of A2AR-D2R heteromerization can explain its low EPS liability.
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Affiliation(s)
- Marta Valle-León
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain
| | - Nil Casajuana-Martin
- Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma Barcelona, Bellaterra, 08193 Barcelona, Spain
| | - Claudia Llinas Del Torrent
- Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma Barcelona, Bellaterra, 08193 Barcelona, Spain
| | - Josep Argerich
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain
| | - Laura Gómez-Acero
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain
| | - Kristoffer Sahlholm
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain; Department of Integrative Medical Biology, Wallenberg Centre for Molecular Medicine, Umeå University, 907 87 Umeå, Sweden; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Sergi Ferré
- Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
| | - Leonardo Pardo
- Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma Barcelona, Bellaterra, 08193 Barcelona, Spain.
| | - Francisco Ciruela
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain.
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Rahman MM, Islam MR, Mim SA, Sultana N, Chellappan DK, Dua K, Kamal MA, Sharma R, Emran TB. Insights into the Promising Prospect of G Protein and GPCR-Mediated Signaling in Neuropathophysiology and Its Therapeutic Regulation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8425640. [PMID: 36187336 PMCID: PMC9519337 DOI: 10.1155/2022/8425640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/23/2022] [Indexed: 11/18/2022]
Abstract
G protein-coupled receptors (GPCRs) are intricately involved in the conversion of extracellular feedback to intracellular responses. These specialized receptors possess a crucial role in neurological and psychiatric disorders. Most nonsensory GPCRs are active in almost 90% of complex brain functions. At the time of receptor phosphorylation, a GPCR pathway is essentially activated through a G protein signaling mechanism via a G protein-coupled receptor kinase (GRK). Dopamine, an important neurotransmitter, is primarily involved in the pathophysiology of several CNS disorders; for instance, bipolar disorder, schizophrenia, Parkinson's disease, and ADHD. Since dopamine, acetylcholine, and glutamate are potent neuropharmacological targets, dopamine itself has potential therapeutic effects in several CNS disorders. GPCRs essentially regulate brain functions by modulating downstream signaling pathways. GPR6, GPR52, and GPR8 are termed orphan GPCRs because they colocalize with dopamine D1 and D2 receptors in neurons of the basal ganglia, either alone or with both receptors. Among the orphan GPCRs, the GPR52 is recognized for being an effective psychiatric receptor. Various antipsychotics like aripiprazole and quetiapine mainly target GPCRs to exert their actions. One of the most important parts of signal transduction is the regulation of G protein signaling (RGS). These substances inhibit the activation of the G protein that initiates GPCR signaling. Developing a combination of RGS inhibitors with GPCR agonists may prove to have promising therapeutic potential. Indeed, several recent studies have suggested that GPCRs represent potentially valuable therapeutic targets for various psychiatric disorders. Molecular biology and genetically modified animal model studies recommend that these enriched GPCRs may also act as potential therapeutic psychoreceptors. Neurotransmitter and neuropeptide GPCR malfunction in the frontal cortex and limbic-related regions, including the hippocampus, hypothalamus, and brainstem, is likely responsible for the complex clinical picture that includes cognitive, perceptual, emotional, and motor symptoms. G protein and GPCR-mediated signaling play a critical role in developing new treatment options for mental health issues, and this study is aimed at offering a thorough picture of that involvement. For patients who are resistant to current therapies, the development of new drugs that target GPCR signaling cascades remains an interesting possibility. These discoveries might serve as a fresh foundation for the creation of creative methods for pharmacologically useful modulation of GPCR function.
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Affiliation(s)
- Md. Mominur Rahman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Md. Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Sadia Afsana Mim
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Nasrin Sultana
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Mohammad Amjad Kamal
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
- King Fahd Medical Research Center, King Abdulaziz University, Saudi Arabia
- Enzymoics, Novel Global Community Educational Foundation, Australia
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005 Uttar Pradesh, India
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
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Ahammad RU, Nishioka T, Yoshimoto J, Kannon T, Amano M, Funahashi Y, Tsuboi D, Faruk MO, Yamahashi Y, Yamada K, Nagai T, Kaibuchi K. KANPHOS: A Database of Kinase-Associated Neural Protein Phosphorylation in the Brain. Cells 2021; 11:47. [PMID: 35011609 PMCID: PMC8750479 DOI: 10.3390/cells11010047] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/19/2021] [Accepted: 12/21/2021] [Indexed: 12/15/2022] Open
Abstract
Protein phosphorylation plays critical roles in a variety of intracellular signaling pathways and physiological functions that are controlled by neurotransmitters and neuromodulators in the brain. Dysregulation of these signaling pathways has been implicated in neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder and schizophrenia. While recent advances in mass spectrometry-based proteomics have allowed us to identify approximately 280,000 phosphorylation sites, it remains largely unknown which sites are phosphorylated by which kinases. To overcome this issue, previously, we developed methods for comprehensive screening of the target substrates of given kinases, such as PKA and Rho-kinase, upon stimulation by extracellular signals and identified many candidate substrates for specific kinases and their phosphorylation sites. Here, we developed a novel online database to provide information about the phosphorylation signals identified by our methods, as well as those previously reported in the literature. The "KANPHOS" (Kinase-Associated Neural Phospho-Signaling) database and its web portal were built based on a next-generation XooNIps neuroinformatics tool. To explore the functionality of the KANPHOS database, we obtained phosphoproteomics data for adenosine-A2A-receptor signaling and its downstream MAPK-mediated signaling in the striatum/nucleus accumbens, registered them in KANPHOS, and analyzed the related pathways.
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Grants
- JP18dm0207005, JP21dm0207075, JP21wm0425017 and JP21wm0425008 Japan Agency for Medical Research and Development
- JP16K18393, JP17H01380, JP17K07383, JP17H02220, JP17K19483, JP18K14849, JP19K16370, JP21K06428 and JP21K06427 Japan Society for the Promotion of Science
- JP17H05561, JP19H05209 and JP21H00196 Ministry of Education, Culture, Sports, Science and Technology
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Affiliation(s)
- Rijwan Uddin Ahammad
- Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan
| | - Tomoki Nishioka
- Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Japan
| | - Junichiro Yoshimoto
- Division of Information Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma 630-0192, Japan
| | - Takayuki Kannon
- Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Science, Kanazawa University, Kanazawa 920-8640, Japan
| | - Mutsuki Amano
- Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan
| | - Yasuhiro Funahashi
- Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Japan
| | - Daisuke Tsuboi
- Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Japan
| | - Md Omar Faruk
- Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan
| | - Yukie Yamahashi
- Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Japan
| | - Kiyofumi Yamada
- Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan
| | - Taku Nagai
- Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), Fujita Health University, Toyoake 470-1192, Japan
| | - Kozo Kaibuchi
- Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan
- Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Japan
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6
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Dopamine signaling impairs ROS modulation by mitochondrial hexokinase in human neural progenitor cells. Biosci Rep 2021; 41:230295. [PMID: 34821365 PMCID: PMC8661505 DOI: 10.1042/bsr20211191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 10/20/2021] [Accepted: 11/09/2021] [Indexed: 12/17/2022] Open
Abstract
Dopamine signaling has numerous roles during brain development. In addition, alterations in dopamine signaling may be also involved in the pathophysiology of psychiatric disorders. Neurodevelopment is modulated in multiple steps by reactive oxygen species (ROS), byproducts of oxidative metabolism that are signaling factors involved in proliferation, differentiation, and migration. Hexokinase (HK), when associated with the mitochondria (mt-HK), is a potent modulator of the generation of mitochondrial ROS in the brain. In the present study, we investigated whether dopamine could affect both the activity and redox function of mt-HK in human neural progenitor cells (NPCs). We found that dopamine signaling via D1R decreases mt-HK activity and impairs ROS modulation, which is followed by an expressive release of H2O2 and impairment in calcium handling by the mitochondria. Nevertheless, mitochondrial respiration is not affected, suggesting specificity for dopamine on mt-HK function. In neural stem cells (NSCs) derived from induced-pluripotent stem cells (iPSCs) of schizophrenia patients, mt-HK is unable to decrease mitochondrial ROS, in contrast with NSCs derived from healthy individuals. Our data point to mitochondrial hexokinase as a novel target of dopaminergic signaling, as well as a redox modulator in human neural progenitor cells, which may be relevant to the pathophysiology of neurodevelopmental disorders such as schizophrenia.
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Botz-Zapp CA, Foster SL, Pulley DM, Hempel B, Bi GH, Xi ZX, Newman AH, Weinshenker D, Manvich DF. Effects of the selective dopamine D 3 receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice. Behav Brain Res 2021; 415:113506. [PMID: 34352292 PMCID: PMC8403645 DOI: 10.1016/j.bbr.2021.113506] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 07/12/2021] [Accepted: 07/27/2021] [Indexed: 12/14/2022]
Abstract
Recent preclinical studies have reported that pretreatment with the novel and highly-selective dopamine D3 receptor (D3R) antagonists R-VK4-40 or VK4-116 attenuates the abuse-related behavioral effects of oxycodone while enhancing its analgesic properties. However, whether these observed effects are generalizable to the broad class of D3R antagonists and/or extend to opioids other than oxycodone has not been extensively explored. The present study sought to assess the impact of pretreatment with another selective D3R antagonist, PG01037, on several behavioral effects of morphine in mice. C57Bl/6 J mice were pretreated with PG01037 (0-10 mg/kg) and tested for 1) hyperlocomotion induced by acute morphine (5.6-56 mg/kg), 2) locomotor sensitization following repeated morphine (56 mg/kg), 3) antinociception following acute morphine (18 mg/kg), and 4) catalepsy following administration of PG01037 alone or in combination with morphine (56 mg/kg). PG01037 dose-dependently attenuated morphine-induced hyperlocomotion and morphine-induced antinociception at doses that did not alter basal locomotion or nociception alone, but did not prevent the induction of locomotor sensitization following repeated morphine administration. Moreover, PG01037 did not induce catalepsy either alone or in combination with morphine. These results suggest that attenuation of acute opioid-induced hyperactivity may be a behavioral effect shared among D3R-selective antagonists, thus supporting continued investigations into their use as potential treatments for opioid use disorder. However, PG01037 is unlike newer, highly-selective D3R antagonists in its capacity to reduce opioid-induced antinociception, indicating that modulation of opioid analgesia may vary across different D3R antagonists.
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Affiliation(s)
- Christian A. Botz-Zapp
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA, USA 30322
| | - Stephanie L. Foster
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA, USA 30322
| | - Desta M. Pulley
- Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, 2 Medical Center Drive, Stratford, NJ, 08084, USA
| | - Briana Hempel
- Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, NIH, DHHS, 333 Cassell Drive, Baltimore, MD, 21224, USA 21224
| | - Guo-Hua Bi
- Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, NIH, DHHS, 333 Cassell Drive, Baltimore, MD, 21224, USA 21224
| | - Zheng-Xiong Xi
- Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, NIH, DHHS, 333 Cassell Drive, Baltimore, MD, 21224, USA 21224
| | - Amy Hauck Newman
- Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, NIH, DHHS, 333 Cassell Drive, Baltimore, MD, 21224, USA 21224
| | - David Weinshenker
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA, USA 30322
| | - Daniel F. Manvich
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA, USA 30322,Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, 2 Medical Center Drive, Stratford, NJ, 08084, USA
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Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor. Biomolecules 2021; 11:biom11040570. [PMID: 33924613 PMCID: PMC8069330 DOI: 10.3390/biom11040570] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/06/2021] [Accepted: 04/09/2021] [Indexed: 02/07/2023] Open
Abstract
The dopamine D2/D3 receptor (D2R/D3R) agonists are used as therapeutics for Parkinson's disease (PD) and other motor disorders. Selective targeting of D3R over D2R is attractive because of D3R's restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the D2R and D3R poses a challenge in the development of D3R selective agonists. To address the ligand selectivity, bitopic ligands were designed and synthesized previously based on a potent D3R-preferential agonist PF592,379 as the primary pharmacophore (PP). This PP was attached to various secondary pharmacophores (SPs) using chemically different linkers. Here, we characterize some of these novel bitopic ligands at both D3R and D2R using BRET-based functional assays. The bitopic ligands showed varying differences in potencies and efficacies. In addition, the chirality of the PP was key to conferring improved D3R potency, selectivity, and G protein signaling bias. In particular, compound AB04-88 exhibited significant D3R over D2R selectivity, and G protein bias at D3R. This bias was consistently observed at various time-points ranging from 8 to 46 min. Together, the structure-activity relationships derived from these functional studies reveal unique pharmacology at D3R and support further evaluation of functionally biased D3R agonists for their therapeutic potential.
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9
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Liu Z, Iyer MR, Godlewski G, Jourdan T, Liu J, Coffey NJ, Zawatsky CN, Puhl HL, Wess J, Meister J, Liow JS, Innis RB, Hassan SA, Lee YS, Kunos G, Cinar R. Functional Selectivity of a Biased Cannabinoid-1 Receptor (CB 1R) Antagonist. ACS Pharmacol Transl Sci 2021; 4:1175-1187. [PMID: 34151207 PMCID: PMC8204328 DOI: 10.1021/acsptsci.1c00048] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Indexed: 12/31/2022]
Abstract
Seven-transmembrane receptors signal via G-protein- and β-arrestin-dependent pathways. We describe a peripheral CB1R antagonist (MRI-1891) highly biased toward inhibiting CB1R-induced β-arrestin-2 (βArr2) recruitment over G-protein activation. In obese wild-type and βArr2-knockout (KO) mice, MRI-1891 treatment reduces food intake and body weight without eliciting anxiety even at a high dose causing partial brain CB1R occupancy. By contrast, the unbiased global CB1R antagonist rimonabant elicits anxiety in both strains, indicating no βArr2 involvement. Interestingly, obesity-induced muscle insulin resistance is improved by MRI-1891 in wild-type but not in βArr2-KO mice. In C2C12 myoblasts, CB1R activation suppresses insulin-induced akt-2 phosphorylation, preventable by MRI-1891, βArr2 knockdown or overexpression of CB1R-interacting protein. MRI-1891, but not rimonabant, interacts with nonpolar residues on the N-terminal loop, including F108, and on transmembrane helix-1, including S123, a combination that facilitates βArr2 bias. Thus, CB1R promotes muscle insulin resistance via βArr2 signaling, selectively mitigated by a biased CB1R antagonist at reduced risk of central nervous system (CNS) side effects.
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Affiliation(s)
- Ziyi Liu
- Laboratory of Physiologic Studies and Section on Cellular Biophotonics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9304, United States
| | - Malliga R Iyer
- Laboratory of Physiologic Studies and Section on Cellular Biophotonics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9304, United States
| | - Grzegorz Godlewski
- Laboratory of Physiologic Studies and Section on Cellular Biophotonics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9304, United States
| | - Tony Jourdan
- Laboratory of Physiologic Studies and Section on Cellular Biophotonics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9304, United States
| | - Jie Liu
- Laboratory of Physiologic Studies and Section on Cellular Biophotonics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9304, United States
| | - Nathan J Coffey
- Laboratory of Physiologic Studies and Section on Cellular Biophotonics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9304, United States
| | - Charles N Zawatsky
- Laboratory of Physiologic Studies and Section on Cellular Biophotonics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9304, United States
| | - Henry L Puhl
- Laboratory of Physiologic Studies and Section on Cellular Biophotonics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9304, United States
| | - Jürgen Wess
- Laboratory of Bioorganic Chemistry, National Institute on Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892-0001, United States
| | - Jaroslawna Meister
- Laboratory of Bioorganic Chemistry, National Institute on Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892-0001, United States
| | - Jeih-San Liow
- Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland 20892-9663, United States
| | - Robert B Innis
- Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland 20892-9663, United States
| | - Sergio A Hassan
- Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States
| | - Yong Sok Lee
- Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States
| | - George Kunos
- Laboratory of Physiologic Studies and Section on Cellular Biophotonics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9304, United States
| | - Resat Cinar
- Laboratory of Physiologic Studies and Section on Cellular Biophotonics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9304, United States
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10
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Lee JH, Shon SY, Jeon W, Hong SJ, Ban J, Lee DS. Discovery of μ,δ-Opioid Receptor Dual-Biased Agonists That Overcome the Limitation of Prior Biased Agonists. ACS Pharmacol Transl Sci 2021; 4:1149-1160. [PMID: 34151205 DOI: 10.1021/acsptsci.1c00044] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Indexed: 11/28/2022]
Abstract
Morphine is widely used in pain management although the risk of side effects is significant. The use of biased agonists to the G protein of μ-opioid receptors has been suggested as a potential solution, although oliceridine and PZM21 have previously failed to demonstrate benefits in clinical studies. An amplification-induced confusion in the process of comparing G protein and beta-arrestin pathways may account for previously biased agonist misidentification. Here, we have devised a strategy to discover biased agonists with intrinsic efficacy. We computationally simulated 430 000 molecular dockings to the μ-opioid receptor to construct a compound library. Hits were then verified experimentally. Using the verified compounds, we performed simulations to build a second library with a common scaffold and selected compounds that showed a bias to μ- and δ-opioid receptors in a cell-based assay. Three compounds (ID110460001, ID110460002, and ID110460003) with a dual-biased agonistic effect for μ- and δ-opioid receptors were identified. These candidates are full agonists for the μ-opioid receptor and show specific binding modes. On the basis of our findings, we expect our novel compounds to act as more biased agonists compared to existing drugs, including oliceridine.
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Affiliation(s)
- Jin Hee Lee
- Research Laboratory, Ildong Pharmaceutical Co., Ltd., 20, Samsung 1-ro 1-gil, Hwaseong 18449, Korea
| | - Suh-Youn Shon
- Research Laboratory, Ildong Pharmaceutical Co., Ltd., 20, Samsung 1-ro 1-gil, Hwaseong 18449, Korea
| | - Woojin Jeon
- Research Laboratory, Ildong Pharmaceutical Co., Ltd., 20, Samsung 1-ro 1-gil, Hwaseong 18449, Korea
| | - Sung-Jun Hong
- Research Laboratory, Ildong Pharmaceutical Co., Ltd., 20, Samsung 1-ro 1-gil, Hwaseong 18449, Korea
| | - Junsu Ban
- Research Laboratory, Ildong Pharmaceutical Co., Ltd., 20, Samsung 1-ro 1-gil, Hwaseong 18449, Korea
| | - Do Sup Lee
- Research Laboratory, Ildong Pharmaceutical Co., Ltd., 20, Samsung 1-ro 1-gil, Hwaseong 18449, Korea
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11
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Wang Q, Zhou Y, Huang J, Huang N. Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor. Pharmaceuticals (Basel) 2021; 14:76. [PMID: 33498477 PMCID: PMC7909583 DOI: 10.3390/ph14020076] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 12/13/2022] Open
Abstract
Since the first characterization of the 5-hydroxytryptamine 2B receptor (5-HT2BR) in 1992, significant progress has been made in 5-HT2BR research. Herein, we summarize the biological function, structure, and small-molecule pharmaceutical ligands of the 5-HT2BR. Emerging evidence has suggested that the 5-HT2BR is implicated in the regulation of the cardiovascular system, fibrosis disorders, cancer, the gastrointestinal (GI) tract, and the nervous system. Eight crystal complex structures of the 5-HT2BR bound with different ligands provided great insights into ligand recognition, activation mechanism, and biased signaling. Numerous 5-HT2BR antagonists have been discovered and developed, and several of them have advanced to clinical trials. It is expected that the novel 5-HT2BR antagonists with high potency and selectivity will lead to the development of first-in-class drugs in various therapeutic areas.
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Affiliation(s)
- Qing Wang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China; (Q.W.); (J.H.)
- National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China;
| | - Yu Zhou
- National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China;
| | - Jianhui Huang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China; (Q.W.); (J.H.)
| | - Niu Huang
- National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China;
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China
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12
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Menniti FS, Chappie TA, Schmidt CJ. PDE10A Inhibitors-Clinical Failure or Window Into Antipsychotic Drug Action? Front Neurosci 2021; 14:600178. [PMID: 33551724 PMCID: PMC7855852 DOI: 10.3389/fnins.2020.600178] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 12/21/2020] [Indexed: 01/21/2023] Open
Abstract
PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is a unique signaling molecule in being highly and nearly exclusively expressed in striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among available behavioral options. Medium spiny neurons are components of either the direct or indirect striatal output pathways. Selective activation of indirect pathway medium spiny neurons by dopamine D2 receptor antagonists is putatively a key element in the mechanism of their antipsychotic efficacy. While PDE10A is expressed in all medium spiny neurons, studies in rodents indicated that PDE10A inhibition has behavioral effects in several key assays that phenocopy dopamine D2 receptor inhibition. This finding gave rise to the hypothesis that PDE10A inhibition also preferentially activates indirect pathway medium spiny neurons, a hypothesis that is consistent with electrophysiological, neurochemical, and molecular effects of PDE10A inhibitors. These data underwrote industry-wide efforts to investigate and develop PDE10A inhibitors as novel antipsychotics. Disappointingly, PDE10A inhibitors from 3 companies failed to evidence antipsychotic activity in patients with schizophrenia to the same extent as standard-of-care D2 antagonists. Given the notable similarities between PDE10A inhibitors and D2 antagonists, gaining an understanding of why only the latter class is antipsychotic affords a unique window into the basis for this therapeutic efficacy. With this in mind, we review the data on PDE10A inhibition as a step toward back-translating the limited antipsychotic efficacy of PDE10A inhibitors, hopefully to inform new efforts to develop better therapeutics to treat psychosis and schizophrenia.
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Affiliation(s)
- Frank S Menniti
- George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, United States
| | - Thomas A Chappie
- Internal Medicine Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA, United States
| | - Christopher J Schmidt
- Pfizer Innovation and Research Lab Unit, Pfizer Worldwide Research and Development, Cambridge, MA, United States
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13
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van Gastel J, Leysen H, Boddaert J, Vangenechten L, Luttrell LM, Martin B, Maudsley S. Aging-related modifications to G protein-coupled receptor signaling diversity. Pharmacol Ther 2020; 223:107793. [PMID: 33316288 DOI: 10.1016/j.pharmthera.2020.107793] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 11/26/2020] [Indexed: 02/06/2023]
Abstract
Aging is a highly complex molecular process, affecting nearly all tissue systems in humans and is the highest risk factor in developing neurodegenerative disorders such as Alzheimer's and Parkinson's disease, cardiovascular disease and Type 2 diabetes mellitus. The intense complexity of the aging process creates an incentive to develop more specific drugs that attenuate or even reverse some of the features of premature aging. As our current pharmacopeia is dominated by therapeutics that target members of the G protein-coupled receptor (GPCR) superfamily it may be prudent to search for effective anti-aging therapeutics in this fertile domain. Since the first demonstration of GPCR-based β-arrestin signaling, it has become clear that an enhanced appreciation of GPCR signaling diversity may facilitate the creation of therapeutics with selective signaling activities. Such 'biased' ligand signaling profiles can be effectively investigated using both standard molecular biological techniques as well as high-dimensionality data analyses. Through a more nuanced appreciation of the quantitative nature across the multiple dimensions of signaling bias that drugs possess, researchers may be able to further refine the efficacy of GPCR modulators to impact the complex aberrations that constitute the aging process. Identifying novel effector profiles could expand the effective pharmacopeia and assist in the design of precision medicines. This review discusses potential non-G protein effectors, and specifically their potential therapeutic suitability in aging and age-related disorders.
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Affiliation(s)
- Jaana van Gastel
- Receptor Biology Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Faculty of Pharmacy, Biomedical and Veterinary Science, University of Antwerp, Antwerp, Belgium
| | - Hanne Leysen
- Receptor Biology Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Faculty of Pharmacy, Biomedical and Veterinary Science, University of Antwerp, Antwerp, Belgium
| | - Jan Boddaert
- Molecular Pathology Group, Faculty of Medicine and Health Sciences, Laboratory of Cell Biology and Histology, Antwerp, Belgium
| | - Laura Vangenechten
- Receptor Biology Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Louis M Luttrell
- Division of Endocrinology, Diabetes & Medical Genetics, Medical University of South Carolina, USA
| | - Bronwen Martin
- Faculty of Pharmacy, Biomedical and Veterinary Science, University of Antwerp, Antwerp, Belgium
| | - Stuart Maudsley
- Receptor Biology Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Faculty of Pharmacy, Biomedical and Veterinary Science, University of Antwerp, Antwerp, Belgium.
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14
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Sommer ME, Selent J, Carlsson J, De Graaf C, Gloriam DE, Keseru GM, Kosloff M, Mordalski S, Rizk A, Rosenkilde MM, Sotelo E, Tiemann JKS, Tobin A, Vardjan N, Waldhoer M, Kolb P. The European Research Network on Signal Transduction (ERNEST): Toward a Multidimensional Holistic Understanding of G Protein-Coupled Receptor Signaling. ACS Pharmacol Transl Sci 2020; 3:361-370. [PMID: 32296774 DOI: 10.1021/acsptsci.0c00024] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Indexed: 12/14/2022]
Abstract
G protein-coupled receptors (GPCRs) are intensively studied due to their therapeutic potential as drug targets. Members of this large family of transmembrane receptor proteins mediate signal transduction in diverse cell types and play key roles in human physiology and health. In 2013 the research consortium GLISTEN (COST Action CM1207) was founded with the goal of harnessing the substantial growth in knowledge of GPCR structure and dynamics to push forward the development of molecular modulators of GPCR function. The success of GLISTEN, coupled with new findings and paradigm shifts in the field, led in 2019 to the creation of a related consortium called ERNEST (COST Action CA18133). ERNEST broadens focus to entire signaling cascades, based on emerging ideas of how complexity and specificity in signal transduction are not determined by receptor-ligand interactions alone. A holistic approach that unites the diverse data and perspectives of the research community into a single multidimensional map holds great promise for improved drug design and therapeutic targeting.
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Affiliation(s)
- Martha E Sommer
- Institute of Medical Physics and Biophysics, Charité-Universitätsmedizin Berlin, Berlin, 10117, Germany.,Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany
| | - Jana Selent
- Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM) - Pompeu Fabra University (UPF), Barcelona, 08003, Spain
| | - Jens Carlsson
- Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, 752 36, Sweden
| | | | - David E Gloriam
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, 1017, Denmark
| | - Gyorgy M Keseru
- Medicinal Chemistry Research Group, Research Center for Natural Sciences (RCNS), Budapest, H-1117, Hungary
| | - Mickey Kosloff
- Department of Human Biology, University of Haifa, Haifa, 3498838, Israel
| | - Stefan Mordalski
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, 1017, Denmark.,Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, 31-343, Poland
| | - Aurelien Rizk
- InterAx Biotech AG, PARK innovAARE, Villigen, 5234, Switzerland
| | - Mette M Rosenkilde
- Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK 2200, Denmark
| | - Eddy Sotelo
- Centro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS) and Facultade de Farmacia. Universidade de Santiago de Compostela, Santiago de compostela, 15782, Spain
| | - Johanna K S Tiemann
- Institute for Medical Physics and Biophysics, Leipzig University, Leipzig, 04109, Germany.,Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Kobenhavn, 2200, Denmark
| | - Andrew Tobin
- The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, U.K
| | - Nina Vardjan
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, 1000, Slovenia.,Laboratory of Cell Engineering, Celica Biomedical, Ljubljana, 1000, Slovenia
| | - Maria Waldhoer
- InterAx Biotech AG, PARK innovAARE, Villigen, 5234, Switzerland
| | - Peter Kolb
- Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, 35039, Germany
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15
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Jordan CJ, Humburg BA, Thorndike EB, Shaik AB, Xi ZX, Baumann MH, Newman AH, Schindler CW. Newly Developed Dopamine D 3 Receptor Antagonists, R-VK4-40 and R-VK4-116, Do Not Potentiate Cardiovascular Effects of Cocaine or Oxycodone in Rats. J Pharmacol Exp Ther 2019; 371:602-614. [PMID: 31562201 PMCID: PMC6863462 DOI: 10.1124/jpet.119.259390] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 09/23/2019] [Indexed: 12/24/2022] Open
Abstract
Opioid and cocaine abuse are major public health burdens. Existing medications for opioid use disorder are limited by abuse liability and side effects, whereas no treatments are currently approved in the United States for cocaine use disorder. Dopamine D3 receptor (D3R) antagonists have shown promise in attenuating opioid and cocaine reward and mitigating relapse in preclinical models. However, translation of D3R antagonists to the clinic has been hampered by reports that the D3R antagonists GSK598,809 (5-(5-((3-((1S,5R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)propyl)thio)-4-methyl-4H-1,2,4-triazol-3-yl)-4-methyloxazole) and SB-277,011A (2-(2-((1r,4r)-4-(2-oxo-2-(quinolin-4-yl)ethyl)cyclohexyl)ethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile) have adverse cardiovascular effects in the presence of cocaine. Recently, we developed two structurally novel D3R antagonists, R-VK4-40 and R-VK4-116, which are highly selective for D3R and display translational potential for treatment of opioid use disorder. Here, we tested whether R-VK4-40 ((R)-N-(4-(4-(2-Chloro-3-ethylphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide) and R-VK4-116 ((R)-N-(4-(4-(3-Chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide) have unwanted cardiovascular effects in the presence of oxycodone, a prescription opioid, or cocaine in freely moving rats fitted with surgically implanted telemetry transmitters. We also examined cardiovascular effects of the D3R antagonist, SB-277,011A, and L-741,626 (1-((1H-indol-3-yl)methyl)-4-(4-chlorophenyl)piperidin-4-ol), a dopamine D2 receptor-selective antagonist, for comparison. Consistent with prior reports, SB-277,011A increased blood pressure, heart rate, and locomotor activity alone and in the presence of cocaine. L-741,626 increased blood pressure and heart rate. In contrast, R-VK4-40 alone dose-dependently reduced blood pressure and heart rate and attenuated oxycodone-induced increases in blood pressure and oxycodone or cocaine-induced increases in heart rate. Similarly, R-VK4-116 alone dose-dependently reduced cocaine-induced increases in blood pressure and heart rate. These results highlight the safety of new D3R antagonists and support the continued development of R-VK4-40 and R-VK4-116 for the treatment of opioid and cocaine use disorders. SIGNIFICANCE STATEMENT: Opioid and cocaine abuse are major public health challenges and new treatments that do not adversely impact the cardiovascular system are needed. Here, we show that two structurally novel dopamine D3 receptor antagonists, R-VK4-40 and R-VK4-116, do not potentiate, and may even protect against, oxycodone- or cocaine-induced changes in blood pressure and heart rate, supporting their further development for the treatment of opioid and/or cocaine use disorders.
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Affiliation(s)
- Chloe J Jordan
- Molecular Targets and Medications Discovery Branch (C.J.J., B.A.H., A.B.S., Z.-X.X., A.H.N.), Designer Drug Research Unit (M.H.B., C.W.S.), and Preclinical Pharmacology Section (E.B.T., C.W.S.), Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
| | - Bree A Humburg
- Molecular Targets and Medications Discovery Branch (C.J.J., B.A.H., A.B.S., Z.-X.X., A.H.N.), Designer Drug Research Unit (M.H.B., C.W.S.), and Preclinical Pharmacology Section (E.B.T., C.W.S.), Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
| | - Eric B Thorndike
- Molecular Targets and Medications Discovery Branch (C.J.J., B.A.H., A.B.S., Z.-X.X., A.H.N.), Designer Drug Research Unit (M.H.B., C.W.S.), and Preclinical Pharmacology Section (E.B.T., C.W.S.), Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
| | - Anver Basha Shaik
- Molecular Targets and Medications Discovery Branch (C.J.J., B.A.H., A.B.S., Z.-X.X., A.H.N.), Designer Drug Research Unit (M.H.B., C.W.S.), and Preclinical Pharmacology Section (E.B.T., C.W.S.), Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
| | - Zheng-Xiong Xi
- Molecular Targets and Medications Discovery Branch (C.J.J., B.A.H., A.B.S., Z.-X.X., A.H.N.), Designer Drug Research Unit (M.H.B., C.W.S.), and Preclinical Pharmacology Section (E.B.T., C.W.S.), Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
| | - Michael H Baumann
- Molecular Targets and Medications Discovery Branch (C.J.J., B.A.H., A.B.S., Z.-X.X., A.H.N.), Designer Drug Research Unit (M.H.B., C.W.S.), and Preclinical Pharmacology Section (E.B.T., C.W.S.), Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
| | - Amy Hauck Newman
- Molecular Targets and Medications Discovery Branch (C.J.J., B.A.H., A.B.S., Z.-X.X., A.H.N.), Designer Drug Research Unit (M.H.B., C.W.S.), and Preclinical Pharmacology Section (E.B.T., C.W.S.), Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
| | - Charles W Schindler
- Molecular Targets and Medications Discovery Branch (C.J.J., B.A.H., A.B.S., Z.-X.X., A.H.N.), Designer Drug Research Unit (M.H.B., C.W.S.), and Preclinical Pharmacology Section (E.B.T., C.W.S.), Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
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16
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Martini ML, Ray C, Yu X, Liu J, Pogorelov VM, Wetsel WC, Huang XP, McCorvy JD, Caron MG, Jin J. Designing Functionally Selective Noncatechol Dopamine D 1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity. ACS Chem Neurosci 2019; 10:4160-4182. [PMID: 31387346 DOI: 10.1021/acschemneuro.9b00410] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Dopamine receptors are important G protein-coupled receptors (GPCRs) with therapeutic opportunities for treating Parkinson's Disease (PD) motor and cognitive deficits. Biased D1 dopamine ligands that differentially activate G protein over β-arrestin recruitment pathways are valuable chemical tools for dissecting positive versus negative effects in drugs for PD. Here, we reveal an iterative approach toward modification of a D1-selective noncatechol scaffold critical for G protein-biased agonism. This approach provided enhanced understanding of the structural components critical for activity and signaling bias and led to the discovery of several novel compounds with useful pharmacological properties, including three highly GS-biased partial agonists. Administration of a potent, balanced, and brain-penetrant lead compound from this series results in robust antiparkinsonian effects in a rodent model of PD. This study suggests that the noncatechol ligands developed through this approach are valuable tools for probing D1 receptor signaling biology and biased agonism in models of neurologic disease.
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Affiliation(s)
- Michael L. Martini
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
- Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Caroline Ray
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, United States
| | - Xufen Yu
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Jing Liu
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Vladimir M. Pogorelov
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, United States
- Departments of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, United States
- Department of Medicine and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, United States
| | - William C. Wetsel
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, United States
- Departments of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, United States
- Department of Medicine and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, United States
| | - Xi-Ping Huang
- Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - John D. McCorvy
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States
| | - Marc G. Caron
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, United States
- Department of Medicine and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, United States
| | - Jian Jin
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
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17
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Komatsu H, Fukuchi M, Habata Y. Potential Utility of Biased GPCR Signaling for Treatment of Psychiatric Disorders. Int J Mol Sci 2019; 20:E3207. [PMID: 31261897 PMCID: PMC6651563 DOI: 10.3390/ijms20133207] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 06/24/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Abstract
Tremendous advances have been made recently in the identification of genes and signaling pathways associated with the risks for psychiatric disorders such as schizophrenia and bipolar disorder. However, there has been a marked reduction in the pipeline for the development of new psychiatric drugs worldwide, mainly due to the complex causes that underlie these disorders. G-protein coupled receptors (GPCRs) are the most common targets of antipsychotics such as quetiapine and aripiprazole, and play pivotal roles in controlling brain function by regulating multiple downstream signaling pathways. Progress in our understanding of GPCR signaling has opened new possibilities for selective drug development. A key finding has been provided by the concept of biased ligands, which modulate some, but not all, of a given receptor's downstream signaling pathways. Application of this concept raises the possibility that the biased ligands can provide therapeutically desirable outcomes with fewer side effects. Instead, this application will require a detailed understanding of the mode of action of antipsychotics that drive distinct pharmacologies. We review our current understanding of the mechanistic bases for multiple signaling modes by antipsychotics and the potential of the biased modulators to treat mental disorders.
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Affiliation(s)
- Hidetoshi Komatsu
- Medical Affairs, Kyowa Pharmaceutical Industry Co., Ltd. (A Lupin Group Company), Osaka 530-0005, Japan.
- Department of Biological Science, Graduate School of Science, Nagoya University, Nagoya City 464-8602, Japan.
| | - Mamoru Fukuchi
- Laboratory of Molecular Neuroscience, Faculty of Pharmacy, Takasaki University of Health and Welfare, Gunma 370-0033, Japan
| | - Yugo Habata
- Department of Food & Nutrition, Yamanashi Gakuin Junior College, Kofu 400-8575, Japan
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18
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Seyedabadi M, Ghahremani MH, Albert PR. Biased signaling of G protein coupled receptors (GPCRs): Molecular determinants of GPCR/transducer selectivity and therapeutic potential. Pharmacol Ther 2019; 200:148-178. [PMID: 31075355 DOI: 10.1016/j.pharmthera.2019.05.006] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 04/26/2019] [Indexed: 02/07/2023]
Abstract
G protein coupled receptors (GPCRs) convey signals across membranes via interaction with G proteins. Originally, an individual GPCR was thought to signal through one G protein family, comprising cognate G proteins that mediate canonical receptor signaling. However, several deviations from canonical signaling pathways for GPCRs have been described. It is now clear that GPCRs can engage with multiple G proteins and the line between cognate and non-cognate signaling is increasingly blurred. Furthermore, GPCRs couple to non-G protein transducers, including β-arrestins or other scaffold proteins, to initiate additional signaling cascades. Receptor/transducer selectivity is dictated by agonist-induced receptor conformations as well as by collateral factors. In particular, ligands stabilize distinct receptor conformations to preferentially activate certain pathways, designated 'biased signaling'. In this regard, receptor sequence alignment and mutagenesis have helped to identify key receptor domains for receptor/transducer specificity. Furthermore, molecular structures of GPCRs bound to different ligands or transducers have provided detailed insights into mechanisms of coupling selectivity. However, receptor dimerization, compartmentalization, and trafficking, receptor-transducer-effector stoichiometry, and ligand residence and exposure times can each affect GPCR coupling. Extrinsic factors including cell type or assay conditions can also influence receptor signaling. Understanding these factors may lead to the development of improved biased ligands with the potential to enhance therapeutic benefit, while minimizing adverse effects. In this review, evidence for ligand-specific GPCR signaling toward different transducers or pathways is elaborated. Furthermore, molecular determinants of biased signaling toward these pathways and relevant examples of the potential clinical benefits and pitfalls of biased ligands are discussed.
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Affiliation(s)
- Mohammad Seyedabadi
- Department of Pharmacology, School of Medicine, Bushehr University of Medical Sciences, Iran; Education Development Center, Bushehr University of Medical Sciences, Iran
| | | | - Paul R Albert
- Ottawa Hospital Research Institute, Neuroscience, University of Ottawa, Canada.
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19
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Lamaa D, Lin HP, Bzeih T, Retailleau P, Alami M, Hamze A. TBAB-Catalyzed Csp
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-N Bond Formation by Coupling Pyridotriazoles with Anilines: A New Route to (2-Pyridyl)alkylamines. European J Org Chem 2019. [DOI: 10.1002/ejoc.201801803] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Diana Lamaa
- BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS; University Paris-Saclay; 92290, Châtenay-Malabry France
| | - Hsin-Ping Lin
- BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS; University Paris-Saclay; 92290, Châtenay-Malabry France
| | - Tourin Bzeih
- BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS; University Paris-Saclay; 92290, Châtenay-Malabry France
| | - Pascal Retailleau
- Institut de Chimie des Substances Naturelles; 91198, Gif-sur-Yvette France
| | - Mouad Alami
- BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS; University Paris-Saclay; 92290, Châtenay-Malabry France
| | - Abdallah Hamze
- BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS; University Paris-Saclay; 92290, Châtenay-Malabry France
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Abstract
A great deal of experimental evidence suggests that ligands can stabilize different receptor active states that go on to interact with cellular signaling proteins to form a range of different complexes in varying quantities. In pleiotropically linked receptor systems, this leads to selective activation of some signaling pathways at the expense of others (biased signaling). This article summarizes the current knowledge about the complex components of receptor systems, the evidence that biased signaling is used in natural physiology to fine-tune signaling, and the current thoughts on how this mechanism may be applied to the design of better drugs. Although this is a fairly newly discovered phenomenon, theoretical and experimental data suggest that it is a ubiquitous behavior of ligands and receptors and to be expected. Biased signaling is simple to detect in vitro and there are numerous methods to quantify the effect with scales that can be used to optimize this activity in structure-activity medicinal chemistry studies. At present, the major hurdle in the application of this mechanism to therapeutics is the translation of in vitro bias to in vivo effect; this is because of the numerous factors that can modify measures of bias in natural physiologic systems. In spite of this, biased signaling still has the potential to justify revisiting of receptor targets previously thought to be intractable and also furnishes the means to pursue targets previously thought to be forbidden due to deleterious physiology (as these may be eliminated through biased signaling).
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Affiliation(s)
- Terry Kenakin
- Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
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21
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Martini ML, Liu J, Ray C, Yu X, Huang XP, Urs A, Urs N, McCorvy JD, Caron MG, Roth BL, Jin J. Defining Structure-Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D 1 Receptor Agonists. J Med Chem 2019; 62:3753-3772. [PMID: 30875219 DOI: 10.1021/acs.jmedchem.9b00351] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
G protein-coupled receptors (GPCRs) are capable of downstream signaling through distinct noncanonical pathways such as β-arrestins in addition to the canonical G protein-dependent pathways. GPCR ligands that differentially activate the downstream signaling pathways are termed functionally selective or biased ligands. A class of novel non-catechol G protein-biased agonists of the dopamine D1 receptor (D1R) was recently disclosed. We conducted the first comprehensive structure-functional selectivity relationship study measuring GS and β-arrestin2 recruitment activities focused on four regions of this scaffold, resulting in over 50 analogs with diverse functional selectivity profiles. Some compounds became potent full agonists of β-arrestin2 recruitment, while others displayed enhanced GS bias compared to the starting compound. Pharmacokinetic testing of an analog with an altered functional selectivity profile demonstrated excellent blood-brain barrier penetration. This study provides novel tools for studying ligand bias at D1R and paves the way for developing the next generation of biased D1R ligands.
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Affiliation(s)
| | | | | | | | - Xi-Ping Huang
- Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States
| | - Aarti Urs
- Department of Pharmacology and Therapeutics, College of Medicine , University of Florida , Gainesville , Florida 32610 , United States
| | - Nikhil Urs
- Department of Pharmacology and Therapeutics, College of Medicine , University of Florida , Gainesville , Florida 32610 , United States
| | - John D McCorvy
- Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.,Department of Cell Biology, Neurobiology and Anatomy , Medical College of Wisconsin , Milwaukee , Wisconsin 53226 , United States
| | | | - Bryan L Roth
- Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States
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22
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Bermudez M, Nguyen TN, Omieczynski C, Wolber G. Strategies for the discovery of biased GPCR ligands. Drug Discov Today 2019; 24:1031-1037. [PMID: 30831262 DOI: 10.1016/j.drudis.2019.02.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 02/13/2019] [Accepted: 02/25/2019] [Indexed: 02/07/2023]
Abstract
G-protein-coupled receptors (GPCRs) represent important drug targets with complex pharmacological characteristics. Biased signaling represents one important dimension, describing ligand-dependent shifts of naturally imprinted signaling profiles. Because biased GPCR modulators provide potential therapeutic benefits including higher efficiencies and reduced adverse effects, the identification of such ligands as drug candidates is highly desirable. This review aims to provide an overview of the challenges and strategies in the discovery of biased ligands. We show different approaches for biased ligand discovery in the example of G-protein-biased opioid analgesics and discuss possibilities to design biased ligands by targeting extracellular receptor regions.
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Affiliation(s)
- Marcel Bermudez
- Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany.
| | - Trung Ngoc Nguyen
- Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany
| | - Christian Omieczynski
- Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany
| | - Gerhard Wolber
- Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany
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23
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Stępnicki P, Kondej M, Kaczor AA. Current Concepts and Treatments of Schizophrenia. Molecules 2018; 23:molecules23082087. [PMID: 30127324 PMCID: PMC6222385 DOI: 10.3390/molecules23082087] [Citation(s) in RCA: 309] [Impact Index Per Article: 44.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 08/10/2018] [Accepted: 08/18/2018] [Indexed: 01/04/2023] Open
Abstract
Schizophrenia is a debilitating mental illness which involves three groups of symptoms, i.e., positive, negative and cognitive, and has major public health implications. According to various sources, it affects up to 1% of the population. The pathomechanism of schizophrenia is not fully understood and current antipsychotics are characterized by severe limitations. Firstly, these treatments are efficient for about half of patients only. Secondly, they ameliorate mainly positive symptoms (e.g., hallucinations and thought disorders which are the core of the disease) but negative (e.g., flat affect and social withdrawal) and cognitive (e.g., learning and attention disorders) symptoms remain untreated. Thirdly, they involve severe neurological and metabolic side effects and may lead to sexual dysfunction or agranulocytosis (clozapine). It is generally agreed that the interactions of antipsychotics with various neurotransmitter receptors are responsible for their effects to treat schizophrenia symptoms. In particular, several G protein-coupled receptors (GPCRs), mainly dopamine, serotonin and adrenaline receptors, are traditional molecular targets for antipsychotics. Comprehensive research on GPCRs resulted in the exploration of novel important signaling mechanisms of GPCRs which are crucial for drug discovery: intentionally non-selective multi-target compounds, allosteric modulators, functionally selective compounds and receptor oligomerization. In this review, we cover current hypotheses of schizophrenia, involving different neurotransmitter systems, discuss available treatments and present novel concepts in schizophrenia and its treatment, involving mainly novel mechanisms of GPCRs signaling.
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Affiliation(s)
- Piotr Stępnicki
- Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland.
| | - Magda Kondej
- Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland.
| | - Agnieszka A Kaczor
- Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland.
- School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland.
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Tan L, Yan W, McCorvy JD, Cheng J. Biased Ligands of G Protein-Coupled Receptors (GPCRs): Structure-Functional Selectivity Relationships (SFSRs) and Therapeutic Potential. J Med Chem 2018; 61:9841-9878. [PMID: 29939744 DOI: 10.1021/acs.jmedchem.8b00435] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
G protein-coupled receptors (GPCRs) signal through both G-protein-dependent and G-protein-independent pathways, and β-arrestin recruitment is the most recognized one of the latter. Biased ligands selective for either pathway are expected to regulate biological functions of GPCRs in a more precise way, therefore providing new drug molecules with superior efficacy and/or reduced side effects. During the past decade, biased ligands have been discovered and developed for many GPCRs, such as the μ opioid receptor, the angiotensin II receptor type 1, the dopamine D2 receptor, and many others. In this Perspective, recent advances in this field are reviewed by discussing the structure-functional selectivity relationships (SFSRs) of GPCR biased ligands and the therapeutic potential of these molecules. Further understanding of the biological functions associated with each signaling pathway and structural basis for biased signaling will facilitate future drug design in this field.
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Affiliation(s)
- Liang Tan
- iHuman Institute , ShanghaiTech University , 393 Middle Huaxia Road , Pudong District, Shanghai 201210 , China
| | - Wenzhong Yan
- iHuman Institute , ShanghaiTech University , 393 Middle Huaxia Road , Pudong District, Shanghai 201210 , China
| | - John D McCorvy
- Department of Cell Biology, Neurobiology and Anatomy , Medical College of Wisconsin , 8701 W. Watertown Plank Road , Milwaukee , Wisconsin 53226 , United States
| | - Jianjun Cheng
- iHuman Institute , ShanghaiTech University , 393 Middle Huaxia Road , Pudong District, Shanghai 201210 , China
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