At the Other Site

At the Other Site
Reported by
Adele Lubell

Posted October 16, 2009


G protein-coupled receptors, or GPCRs, are the most popular and successful target class for drug discovery and development. This class of receptors is involved in several disease states such as heart failure, chronic pain, neuropsychiatric disorders, and obesity. The classic approach to receptor-based drug design has been to identify compounds that interact with the orthosteric site on a receptor target—that is, competitively with the endogenous agonist—either to activate or to block the activation of the receptor.

But there is an alternative. A drug can act at another site, or allosteric site, distant from the orthosteric site to activate a receptor. The field of allosteric modulation of GPCRs has moved forward in the last several years.

The May 24, 2005, meeting of the Academy's Biochemical Pharmacology Discussion Group kicked off with a review of basic theory and was succeeded by a discussion of more specific applications of allosteric modulation of GPCR signals to developing drugs.

Use the tabs above to find a meeting report and multimedia from this event.

Web Sites

GPCRDB: Information system for G protein-coupled receptors
Hosted by the Centre for Molecular and Biomolecular Informatics (CMBI) in the Netherlands, this site is a repository for data concerning GPCR structure and function. Contains links to other resources and articles written by GPCRDB participants.

A comprehensive database of chemical, natural ligand, and biological information on the 297 known human rhodopsin-like GPCRs. Access to data requires a subscription.

Scientist Solutions
The international Web forum has a page dedicated to work on GPCRs.


George, S. R., B. F. O'Dowd & D. R. Sibley, Eds. 2005. G Protein-Coupled Receptor-Protein Interactions. Wiley-Liss, New York.

Haga, T. & S. Takeda, Eds. 2005. G Protein-Coupled Receptors. CRC Press, Boca Raton, FL.

Iyengar, R. & J. D. Hildebrandt, Eds. 2001. G Protein Pathways, Part A: Receptors. Academic Press.

Pangalos, M. N. & C. Davies, Eds. 2002. Understanding G Protein-Coupled Receptors and Their Role in the CNS. Oxford University Press, New York.

Wess, J. 1999. Structure-Function Analysis of G Protein-Coupled Receptors. Wiley-Liss, New York.

Journal Articles

Affinity or Cooperativity: Considerations for Allosteric Modulators at GPCRs

Christopoulos, A. & T. Kenakin. 2002. G protein-coupled receptor allotsterism and complexing. Pharmacol. Rev. 54: 323.374. Full Text

Lazareno, S., A. Popham & N. J. Birdsall. 2004. Progress toward a high-affinity allosteric enhancer at muscarinic M1 receptors. J. Mol. Neurosci. 20: 363-367.

Lazareno, S. V. Dolezal, A. Popham & N. J. Birdsall. 2004. Thiochrome enhances acetylcholine affinity at muscarinic M4 receptors: receptor subtype selectivity via cooperativity rather than affinity. Mol. Pharmacol. 65: 257-266. Full Text

Trankle, C., A. Dittmann, U. Schulz et al. 2005. Atypical muscarinic allosteric modulation: cooperativity between modulators and their atypical binding topology in muscarinic M2 and M2/M5 chimeric receptors. Mol. Pharmacol. (PDF, 2.57 MB) Full Text

The Activation Mechanism of Metabotropic Glutamate Receptors

Galvez, T. & J. P. Pin. 2003. How do G-protein-coupled receptors work? The case of metabotropic glutamate and GABA receptors. Med Sci (Paris) 19: 559-565.

Goudet, C., F. Gaven, J. Kniazeff et al. 2003. Heptahelical domain of metabotropic glutamate receptor 5 behaves like rhodopsin-like receptors. Proc. Natl. Acad. Sci. USA 101: 378-383. Full Text

Goudet, C., J. Kniazeff, V. Hlavackova et al. 2005. Asymmetric functioning of dimeric metabotropic glutamate receptors disclosed by positive allosteric modulators. J. Biol. Chem. 280: 24380-24385.

Havlickova, M., J. Blahos, I. Brabet et al. 2003. The second intracellular loop of metabotropic glutamate receptors recognizes C termini of G-protein alpha-subunits. J. Biol. Chem. 278: 35063-35070. Full Text

Hlavackova, V., C. Goudet, J. Kniazeff et al. 2005. Evidence for a single heptahelical domain being turned on upon activation of a dimeric GPCR. EMBO J. 24: 499-509.

Kniazeff, J., A. S. Bessis, D. Maurel et al. 2004. Closed state of both binding domains of homodimeric mGlu receptors is required for full activity. Nat. Struct. Mol. Biol. 11: 706-713.

Parmentier, M. L., L. Prezeau, J. Bockaert & J. P. Pin. 2002. A model for the functioning of family 3 GPCRs. Trends Pharmacol. Sci. 23: 268-274.

Pin, J. P. & F. Archer. 2002. The metabotropic glutamate receptors: structure, activation, mechanism, and pharmacology. Curr. Drug Targets CNS Neurol. Disord. 1: 297-317.

Triballeau, N., F. Archer, I. Brabet et al 2005. Virtual screening workflow development guided by the "receiver operating characteristic" curve approach. Application to high-throughput docking on metabotropic glutamate receptor subtype 4. J. Med. Chem. 48: 2534-2547.

Project SUPREMA, or How 11-CIS-Retinal Finds Its Binding Site in Rhodopsin

Menon, S. T., M. Ham & T. P. Sakmar. 2001. Rhodopsin: structural basis of molecular physiology. Physiol. Rev. 81: 1659-1688. Full Text

Sakmar, T. P., S. T. Menon, E. P. Marin & E. S. Awad. 2002. Rhodopsin: insights from recent structural studies. Annu. Rev. Biophys. Biomol. Struct. 31: 443-484.

Role of Multiple GPCR Activation States in the Effects of Hallucinogens and Dopamine Agonists

Almaula, N., B. J. Ebersole, D. Zhang et al. 1996. Mapping the binding site pocket of the serotonin 5-hydroxytryptamine2A receptor. Ser3.36(159) provides a second interaction site for the protonated amine of serotonin but not of lysergic acid diethylamide or bufotenin. J. Biol. Chem. 271: 14672-14675. Full Text

Gonzalez-Maeso, J., T. Yuen, B. Ebersole et al. 2003. Transcriptome fingerpints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J. Neurosci. 23: 8836-8843. Full Text

Sealfon, S. C. 2005. G protein-coupled receptors. Sci STKE. 279: tr11.

Allosteric Modulation of Adenosine Receptors

Gao, Z. G., N. Melman, A. Erdman et al. 2003. Differential allosteric modulation by amiloride analogues of agonist and antagonist binding at A(1) and A(3) adenosine receptors. Biochem. Pharmacol. 65: 525-534.

Gao, Z. G., J. E. Van Muijlwijk-Koezen, A. Chen et al. 2001. Allosteric modulation of A(3) adenosine receptors by a series of 3-(2-pyridinyl)isoquinolone derivatives. Mol. Pharmacol. 60: 1057-1063. Full Text

Gao, Z. G., Q. Jiang, K. A. Jacobson & A. P. Ijzerman. Site-directed mutagenesis studies of human A(2A) adenosine receptors: involvement of glu(13) and his(278) in ligand binding and sodium modulation. Biochem. Pharmacol. 60: 661-668.

Gao, Z. G., S. G. Kim, K. A. Soltysiak et al. 2002. Selective allosteric enhancement of agonist binding and function at human A3 adenosine receptors by a series of imidazoquinoline derivatives. Mol. Pharmacol. 62: 81-89. Full Text

Gao, Z. G., S. K. Kim, A. S. Gross et al. 2003. Identification of essential residues involved in the allosteric modulation of the human A(3) adenosine receptor. Mol. Pharm. 63: 1021-1031. Full Text

Allosteric Modulation of Muscarinic Receptors

Bymaster, F. P., D. L. McKinzie, C. C. Felder & J. Wess. 2003. Use of M1-M5 muscarinic receptor knockout mice as novel tools to delineate the physiological roles of the muscarinic cholinergic system. Neurochem. Res. 28: 437-442.

Bymaster, F. P., P. A. Carter, L. Zhang et al. 2001. Investigations into the physiological role of muscarinic M2 and M4 muscarinic and M4 receptor subtypes using receptor knockout mice. Life Sci. 68: 2473-2479.

Felder, C. C. 2004. Strategic Research Institute G-Protein-Coupled Receptors Drug Discovery World Summit. Expert Opin. Investig. Drugs. 13: 1071-1074.

Felder, C. C. 1995. Muscarinic acetylcholine receptors: signal transduction through multiple effectors. FASEB J. 9: 619-625. (PDF, 1.85 MB) Full Text

Felder, C. C., A. C. Porter, T. L. Skillman et al. 2001. Elucidating the role of muscarinic receptors in psychosis. Life Sci. 68: 2605-2613.

Hemricke-Luecke, S. K., F. P. Bymastaer, D. C. Evans et al. 2002. Muscarinic agonist-mediated increases in serum corticosterone levels are abolished in m(2) muscarinic acetylcholine receptor knockout mice. J. Pharmacol. Exp. Ther. 303: 99-103. Full Text

Kohn, E. C., R. Alessandro, J. Probst et al. 1996. Identification and molecular characterization of a m5 muscarinic receptor in A2058 human melanoma cells. Coupling to inhibition of adenylyl cyclase and stimlation of phospholipase A2. J. Biol. Chem. 271: 17476-17484. Full Text

Tzavara, E. T., F. P. Bymaster, C. C. et al. 2003. Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4, and M2/M4 muscarinic receptor knockout mice. Mol. Psychiatry 8: 673-679.

Wess, J., A. Duttaroy, W. Zhang et al. 2003. M1-M5 muscarinic receptor knowckout mice as novel tools to study the physiological roles of the muscarininc cholinergic system. Receptors Channels 9: 279-290.

Metabotropic Glutamate Receptors and the Treatment of Schizophrenia and Parkinson's Disease

Kinnet, G. G., J. A. O'Brien, W. Lemaire. 2005. A novel selective positive allosteric modulator of metabotropc glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. J. Pharmacol. Exp. Ther. 313: 199-203.

Marino, M. J., D. L. Williams Jr., J. A. O'Brien et al. 2003. Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment. Proc. Natl. Acad. Sci. USA 100: 13668-13673. Full Text

Martino, M. J. & J. P. Conn. 2002. Modulation of the basal ganglia by metabotropic glutamate receptors: potential for novel therapeutics. Curr. Drug Targets CNS Neurol. Disord. 1: 239-250.


Nigel Birdsall, PhD

National Institute for Medical Research, UK
email | web site | publications

Nigel Birdsall is program leader in the division of physical biochemistry at the National Institute for Medical Research and is an honorary reader in pharmacology at University College, London.

Birdsall received his graduate and postgraduate degrees from Cambridge University. After postdoctoral research on the chemical mechanisms of carcinogenesis at the Sloan-Kettering Institute for Cancer Research in New York, he returned to Cambridge to work at the new MRC Molecular Pharmacology Unit. There he investigated the structure of lipids and lipid-protein interactions in membranes, primarily using NMR techniques. He then relocated to the National Institute for Medical Research at Mill Hill and began to investigate the detailed binding and functional properties of G protein-coupled receptors, especially muscarinic acetylcholine receptors.

Jean-Philippe Pin, PhD

Institut de Genomique Fonctionnelle
email | web site | publications

Jean-Philippe Pin is the research director of the Centre National de la Recherche Scientifique (CNRS) as well as the head of the molecular pharmacology department at the Institute of Functional Genomics. His research efforts are focused on the activation mechanism of class C GPCRs, mostly mGlu and GABAB receptors, and on their regulation by intracellular proteins.

Pin received his PhD in molecular biology from the University of Science and Technology in Montpellier, France, while working in a CNRS unit. He was part of the team that discovered the metabotropic glutamate receptors. He then participated in the demonstration of synergism between various glutamate receptor subtypes for the activation of phospholipase A2. In 1990 he worked on identifying new mGlu receptor splice variants at the Salk Institute. He went on to set up a research team working on the structure function relationship of mGlu receptors within a CNRS laboratory headed by J. Bockaert in Montpellier. Among other important findings, he demonstrated mGlu receptor constitutive activity can be regulated by intracellular proteins.

Thomas P. Sakmar, MD

The Rockefeller University
email | web site | publications

Thomas Sakmar is Richard M. and Isabel P. Furlaud Professor at the Rockefeller University. He and members of his lab study the vertebrate visual proteins rhodopsin and transducin as a model system for structure-function studies of the molecular mechanism of transmembrane signaling. He is also interested in identifying specific domains of rhodopsin and transducin that interact during signal transduction, and in the actions of other G protein-coupled receptors.

Sakmar earned his MD degree at the University of Chicago before completing a medical residency at the Massachusetts General Hospital, Boston. He conducted postdoctoral research in the laboratory of H. Gobind Khorana in the departments of chemistry and biology at the Massachusetts Institute of Technology.

Stuart C. Sealfon, MD

Mount Sinai School of Medicine
email | web site | publications

Stuart Sealfon is the Saunders Family Professor of Neurology and a professor of neurobiology, biochemistry, and pharmacology at Mount Sinai School of Medecine. He is the director of research in the department of neurology; he also codirects the interdepartmental Center for Translational Systems Biology.

Sealfon received his medical degree from Columbia University and completed his medical and neurology residency training at Massachusetts General Hospital. After a postdoctoral fellowship in molecular neuroendocrinology at Mount Sinai, he remained as a faculty member. His laboratory studies the mechanisms underlying the decoding of extracellular stimuli to generate specific cellular responses in specific endocrine, neural, and immune experimental systems. Principal areas of study include the signaling mechanisms underlying the biosynthetic responses in the gonadotrope modulated by the GnRH receptor, the mechanism of action of serotonergic hallucinogens in cortical neurons, and viral stimulus decoding by dendritic immune cells.

Kenneth A. Jacobson, PhD

National Institute of Diabetes & Digestive & Kidney Diseases, NIH
email | web site | publications

Kenneth Jacobson is chief of the molecular recognition section of the laboratory of bioorganic chemistry at NIH and director of the Chemical Biology Core Facility, both at NIDDK, National Institutes of Health. As a medicinal chemist, Jacobson investigates the structure and pharmacology of G protein-coupled receptors; he has a particular interest in receptors for adenosine and purine and pyrimidine nucleotides. Three agents developed in the Jacobson lab have entered clinical trials for cancer, rheumatoid arthritis, and cystic fibrosis.

Jacobson received his PhD in chemistry from the University of California, San Diego in 1981. He was a Bantrell Fellow at Weizmann Institute in Rehovot, Israel for two years. He received numerous awards, such as the premier international award of the Purine Club in 1996, the Roon Award at Scripps Research Institute in 2001, and the Hillebrand Prize of the Chemical Society of Washington in 2003. Jacobson has also served as chair of the medicinal chemistry division of ACS and as consultant to the pharmaceutical industry. He has authored or coauthored over 400 publications, has been an editor for three books on the pharmacology nucleosides and nucleotides, and is listed as inventor on 43 patents.

Christian C. Felder, PhD

Eli Lilly
email | publications

Christian Felder studies the mechanisms through which the muscarinic and cannabinoid classes of G protein-coupled receptors operate. He received his PhD in biochemistry from Georgetown University before joining Julius Axelrod's lab at the National Institute of Mental Health as a staff fellow in 1987. He became a senior staff fellow in 1990, and later served as chief of the unit on cellular and molecular signaling. Felder joined Eli Lilly & Company in 1998, and is currently director of neuroscience research in the company’s neuroscience division.

P. Jeffrey Conn, PhD

Vanderbilt University School of Medicine
email | web site | publications

Jeffrey Conn recently moved to Vanderbilt University to start a new program in translational neuropharmacology, the primary mission of which is to promote translation of advances in basic science to novel therapeutics agents. Conn also serves as director of the Vanderbilt Institute for Chemical Biology Program in Drug Discovery.

Conn received his PhD in pharmacology in 1986 from Vanderbilt University and pursued postdoctoral studies in the department of pharmacology at Yale University, where he focused his on the roles of G protein-coupled receptors and second messenger systems in regulating neuronal function. Conn went on to join the faculty of the department of pharmacology at Emory University; he rose to the rank of full professor and established himself as a leader in the field of metabotropic glutamate receptors and neuromodulation in mammalian brain. In 2000, Conn moved to Merck and Company to assume the position of senior director of neuroscience and head of the department of neuroscience at Merck's site in West Point, Pennsylvania.

Adele Lubell

Adele Lubell had a career as a science writer and over 25 publications to her credit when she started doctoral studies in cell and molecular biology in 1993 at St. John's University in New York City. She was awarded the doctorate in 1998 for her work on the signaling pathways of diabetes. She currently consults on various writing and science projects for industry and the media.