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Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

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Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives 0031-6997/11/6301-59–126$20.00 PHARMACOLOGICAL REVIEWS Vol. 63, No. 1 Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics 2501/3659116 Pharmacol Rev 63:59–126, 2011 Printed in U.S.A. ASSOCIATE EDITOR: DAVID R. SIBLEY Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives Stephan Urwyler Department of Chemistry and Biochemistry, University of Berne, Berne, Switzerland Abstract ............................................................................... 60 I. Introduction............................................................................ 60 Downloaded from A. Allosteric modulation of receptor activation—an appealing therapeutic principle ........... 60 B. Family C G protein-coupled receptors, a promising group of new drug targets ............. 62 C. Allosteric receptor modulation in the light of theoretical receptor models.................. 64 D. Strategies for discovering allosteric modulators ......................................... 65 II. Allosteric ligands for taste receptors: not only the proof of concept ........................... 66 pharmrev.aspetjournals.org A. Taste—more than just a pleasure ..................................................... 66 B. Molecular mechanisms of sweet and umami taste sensing ............................... 67 C. Possible benefits of allosteric modulators for taste receptors ........................... 70 III. Allosteric modulators allow for subtype selectivity among multiple metabotropic glutamate receptors............................................................................... 71 A. Allosteric ligands for group I metabotropic glutamate receptors: the first success stories .... 71 1. Noncompetitive mGlu5 receptor antagonists turned out to be prototype allosteric mGlu receptor modulators ............................................................... 71 2. Positive allosteric mGlu5 receptor modulators ....................................... 79 at Duke University on June 19, 2012 3. Allosteric modulators of the mGlu1 receptor ......................................... 82 a. Negative allosteric modulators of the mGlu1 receptor.............................. 82 b. Positive allosteric modulators of the mGlu1 receptor .............................. 86 4. Localization of allosteric binding sites at group I mGlu receptors and molecular mechanisms of modulation......................................................... 87 B. Allosteric modulators of group II metabotropic glutamate receptors....................... 89 C. Allosteric ligands acting at group III metabotropic glutamate receptors ................... 95 IV. GABAB receptor function involves allosteric interactions across a heterodimer ................ 100 A. GABAB receptor structure and function................................................ 100 B. The discovery and early characterization of allosteric GABAB receptor modulators ......... 102 C. Interactions between allosteric and orthosteric ligand binding sites: mapping of the allosteric modulator site on GABAB receptors .......................................... 104 D. GABAB receptor modulation in cellular and physiological assay systems: effects of allosteric modulators on receptor desensitization........................................ 105 E. Modulation of GABAB receptor function by other mechanisms and other agents ........... 106 F. Effects of allosteric GABAB receptor modulators in vivo; possible therapeutic applications ........ 106 V. Allosteric modulators of the calcium-sensing receptor: the first clinical success................ 108 A. The role of the calcium-sensing receptor in calcium homeostasis in health and disease ..... 108 B. The structure and function of the calcium sensing receptor: interaction of the receptor with divalent cations and amino acids ................................................. 109 C. Allosteric modulators of the calcium sensing receptor: “Calcimimetics” and “Calcilytics” .... 110 D. In vivo effects of allosteric calcium sensing receptor modulators in animals................ 114 Address correspondence to: Dr. Stephan Urwyler, Department of Chemistry and Biochemistry, University of Berne, P/A Weissensteinweg 3, CH-3303 Jegenstorf, Switzerland. E-mail: [email protected] This article is available online at http://pharmrev.aspetjournals.org. doi:10.1124/pr.109.002501. 59 60 URWYLER E. The effects of calcimimetics and calcilytics in humans: from proof of concept to clinical application.......................................................................... 114 VI. Summary, highlights, and outlook..................................................... 115 Acknowledgments....................................................................... 117 References ............................................................................. 117 Abstract——Allosteric receptor modulation is an at- activation mechanism. Mutational analysis and chime- tractive concept in drug targeting because it offers ric constructs have revealed that allosteric modula- important potential advantages over conventional or- tors of the calcium-sensing, metabotropic glutamate thosteric agonism or antagonism. Allosteric ligands and GABAB receptors bind to the seven transmem- modulate receptor function by binding to a site dis- brane domain, through which they modify signal tinct from the recognition site for the endogenous ag- transduction after receptor activation. This is in con- onist. They often have no effect on their own and trast to taste-enhancing molecules, which bind to dif- therefore act only in conjunction with physiological ferent parts of sweet and umami receptors. The complexity receptor activation. This article reviews the current of interactions between orthosteric and allosteric ligands status of allosteric modulation at family C G-protein is revealed by a number of adequate biochemical and elec- Downloaded from coupled receptors in the light of their specific struc- trophysiological assay systems. Many allosteric family C tural features on the one hand and current concepts in GPCR modulators show in vivo efficacy in behavioral receptor theory on the other hand. Family C G-pro- models for a variety of clinical indications. The positive tein-coupled receptors are characterized by a large allosteric calcium sensing receptor modulator cinacalcet extracellular domain containing the orthosteric ago- is the first drug of this type to enter the market and there- nist binding site known as the “venus flytrap module” fore provides proof of principle in humans. because of its bilobal structure and the dynamics of its pharmrev.aspetjournals.org I. Introduction dently of its physiological state, a positive allosteric mod- A. Allosteric Modulation of Receptor Activation—an ulator will frequently not stimulate the receptor by itself, Appealing Therapeutic Principle but only enhance the function of receptors activated by endogenous agonist. Thus, a positive allosteric modulator The concept of allosteric receptor modulation in drug acts much more in concert with the temporal and spatial targeting has attracted considerable interest in recent organization of physiological receptor activation and is at Duke University on June 19, 2012 years. On the one hand, this is probably because of the therefore expected to have a much lower side effect poten- clinical success of the sedative/anxiolytic benzodiaz- tial than orthosteric agonists. For example, the positive epines, which were introduced into clinical use decades allosteric GABAB receptor modulators 2,6-di-tert-butyl-4- ago. They remain the pioneer example of drugs acting as (3-hydroxy-2,2-dimethylpropyl)phenol (CGP79301) and allosteric modulators, in this case enhancing the func- tion of the ionotropic GABAA receptor (Mo¨hler, 2006). 1Abbreviations: 3-MPPTS, 2,2,2-trifluoro-N-[3-(2-methoxyphenoxy) On the other hand, drugs acting in a similar manner at phenyl]-N-(pyridin-3-ylmethyl)ethanesulfonamide; 5MPEP, 5-methyl-6- other receptors, including G-protein-coupled receptors, (phenylethynyl)-pyridine; 6-OHDA, 6-hydroxydopamine; 7TM, 7-trans- are undoubtedly of great potential (Conn et al., 2009a; membrane; ABP688, 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2- De Amici et al., 2010), and modern drug discovery tech- enone-O-methyl-oxime; ACPT-II, (1R,3R,4S)-1-aminocyclopentane-1, 3,4-tricarboxylic acid; ADX47273, S-(4-fluorophenyl)-{3-[3-(4-fluoro- niques have already allowed the identification of many phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone; AMN082, N, such compounds in recent years. “Allosteric” (from NЈ-dibenzhydrylethane-1,2-diamine dihydrochloride; AMPA, ␣-amino-3- Greek “␣␭␭␱” meaning other and “␴␶␧␳␧␱” meaning ob- hydroxy-5-methyl-4-isoxazolepropionic acid; BAY36-7620, (3aS,6aS)- ject, shape) drugs are compounds that act at a site on a hexahydro-5-methylene-6a-(2-naphthalenylmethyl)-1H-cyclopenta given receptor that is topographically distinct from the [c]furan-1-one; BHF177,N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl- ␱␳␶␩␱ 5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine; BHK, baby hamster “orthosteric” (“ “ meaning correct) recognition site kidney; BINA, biphenylindanone A; CA, cornu ammonis; CaSR, calcium- for the natural or exogenous agonists or competitive sensing receptor; CBiPES, N-(4Ј-cyano-[1,1Ј-biphenyl]-3-yl-N-(3-pyridinyl- antagonists. They act primarily by changing the three- methyl)-ethanesulfonamide hydrochloride; CDPPB, 3-cyano-N-(1, dimensional receptor conformation and thereby
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