Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-77c89778f8-gvh9x Total loading time: 0 Render date: 2024-07-18T18:28:17.182Z Has data issue: false hasContentIssue false

13 - Assessing allosteric ligand-receptor interactions

from PART IV - LIGAND PHARMACOLOGY OF GPCRS

Published online by Cambridge University Press:  05 June 2012

By
Ivan Toma Vranesic  and
Daniel Hoyer
Edited by
Sandra Siehler  and
Graeme Milligan
Ivan Toma Vranesic
Affiliation:
Novartis Institutes for BioMedical Research
Daniel Hoyer
Affiliation:
Novartis Institutes for BioMedical Research
Sandra Siehler
Affiliation:
Novartis Institute for Biomedical Research
Graeme Milligan
Affiliation:
University of Glasgow
Get access

Summary

A summary is not available for this content so a preview has been provided. Please use the Get access link above for information on how to access this content.
Image of the first page of this content. For PDF version, please use the ‘Save PDF’ preceeding this image.'
Type
Chapter
Information
G Protein-Coupled Receptors
Structure, Signaling, and Physiology
 , pp. 247 - 269
Publisher: Cambridge University Press
Print publication year: 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Bartfai, T., Benovic, J. L., Bockaert, J., Bond, R. A., Bouvier, M., Christopoulos, A., Civelli, O., Devi, L. A., George, S. R., Inui, A., Kobilka, B., Leurs, R., Neubig, R., Pin, J. P., Quirion, R., Roques, B. P., Sakmar, T. P., Seifert, R., Stenkamp, R. E . & Strange, P. G. (2004) The state of GPCR research in 2004. Nature Reviews Drug Discovery, 3, 574–626.Google Scholar
Birdsall, N. J. M., Cohen, F., Lazareno, S. & Matsui, H. (1995) Allosteric regulation of g-protein-linked receptors. Biochemical Society Transactions, 23, 108–111.CrossRefGoogle ScholarPubMed
Lazareno, S. & Birdsall, N. J. M. (1995) Detection, quantitation, and verification of allosteric interactions of agents with labeled and unlabeled ligands at G-protein-coupled receptors – interactions of strychnine and acetylcholine at muscarinic receptors. Molecular Pharmacology, 48, 362–378.Google ScholarPubMed
Lazareno, S., Popham, A. & Birdsall, N. J. M. (2000) Allosteric interactions of staurosporine and other indolocarbazoles with N-[methyl-h-3] scopolamine and acetylcholine at muscarinic receptor subtypes: Identification of a second allosteric site. Molecular Pharmacology, 58, 194–206.CrossRefGoogle Scholar
Lazareno, S., Popham, A. & Birdsall, N. J. M. (2002) Analogs of WIN 62,577 define a second allosteric site on muscarinic receptors. Molecular Pharmacology, 62, 1492–1505.CrossRefGoogle ScholarPubMed
Lazareno, S., Dolezal, V., Popham, A. & Birdsall, N. J. M. (2004) Thiochrome enhances acetylcholine affinity at muscarinic m-4 receptors: Receptor subtype selectivity via cooperativity rather than affinity. Molecular Pharmacology, 65, 257–266.CrossRefGoogle Scholar
Monod, J., Wyman, J. & Changeux, J. P. (1965) On nature of allosteric transitions – a plausible model. J. Mol. Biol., 12, 88-&.CrossRefGoogle ScholarPubMed
Christopoulos, A. (2006) Non-classical modes of signaling by 5ht(2c) receptors. Journal of Pharmacological Sciences, 101, 55–55.Google Scholar
Gilchrist, A. (2007) Modulating G-protein-coupled receptors: From traditional pharmacology to allosterics. Trends in Pharmacological Sciences, 28, 431–437.CrossRefGoogle ScholarPubMed
Christopoulos, A. (2009) The impact of allosteric modulation of G-protein-coupled receptors on drug discovery. Journal of Biomolecular Screening, 14, 901–901.Google Scholar
Leff, P. (1995) The 2-state model of receptor activation. Trends in Pharmacological Sciences, 16, 89–97.CrossRefGoogle Scholar
Scaramellini, C. & Leff, P. (1998) A three-state receptor model: Predictions of multiple agonist pharmacology for the same receptor type. Advances in Serotonin Receptor Research – Molecular Biology, Signal Transduction, and Therapeutics, 861, 97–103.Google ScholarPubMed
Strange, P. G. (1998) Three-state and two-state models. Trends in Pharmacological Sciences, 19, 85–86.CrossRefGoogle ScholarPubMed
Black, J. W. & Leff, P. (1983) Operational models of pharmacological agonism. Proc. R. Soc. Lond. Ser. B-Biol. Sci., 220, 141–162.CrossRefGoogle ScholarPubMed
Black, J. W., Leff, P., Shankley, N. P. & Wood, J. (1985) An operational model of pharmacological agonism – the effect of e/[a] curve shape on agonist dissociation-constant estimation. British Journal of Pharmacology, 84, 561–571.CrossRefGoogle Scholar
Del Castillo, J. & Katz, B. (1957) Interaction at end-plate receptors between different choline derivatives. Proc. R. Soc. Lond. Ser. B-Biol. Sci., 146, 369–380.CrossRefGoogle ScholarPubMed
Costa, T. & Herz, A. (1989) Antagonists with negative intrinsic activity at delta-opioid receptors coupled to GTP-binding proteins. Proceedings of the National Academy of Sciences of the United States of America, 86, 7321–7325.CrossRefGoogle ScholarPubMed
Kjelsberg, M. A., Cotecchia, S., Ostrowski, J., Caron, M. G. & Lefkowitz, R. J. (1992) Constitutive activation of the alpha-1b-adrenergic receptor by all amino-acid substitutions at a single site – evidence for a region which constrains receptor activation. Journal of Biological Chemistry, 267, 1430–1433.Google Scholar
Neubig, R. R., Spedding, M., Kenakin, T. & Christopoulos, A. (2003) International union of pharmacology committee on receptor nomenclature and drug classification. Xxxviii. Update on terms and symbols in quantitative pharmacology. Pharmacological Reviews, 55, 597–606.CrossRefGoogle ScholarPubMed
Smit, M. J., Vischer, H. F., Bakker, R. A., Jongejan, A., Timmerman, H., Pardo, L. & Leurs, R. (2007) Pharmacogenomic and structural analysis of constitutive G protein-coupled receptor activity. Annual Review of Pharmacology and Toxicology, 47, 53–87.CrossRefGoogle ScholarPubMed
Herrick-Davis, K., Grinde, E. & Niswander, C. M. (1999) Serotonin 5-HT2c receptor RNA editing alters receptor basal activity: Implications for serotonergic signal transduction. Journal of Neurochemistry, 73, 1711–1717.CrossRefGoogle ScholarPubMed
DeLean, A., Stadel, J. M. & Lefkowitz, R. J. (1980a) A ternary complex model explains the agonist-specific binding-properties of the adenylate cyclase-coupled beta-adrenergic-receptor. Journal of Biological Chemistry, 255, 7108–7117.Google Scholar
DeLean, A., Stadel, J. M. & Lefkowitz, R. J. (1980b) Ternary complex model explains the specific binding-properties of beta-adrenergic agonists. Federation Proceedings, 39, 517–517.Google Scholar
Kent, R. S., Delean, A. & Lefkowitz, R. J. (1980) Quantitative-analysis of beta-adrenergic-receptor interactions – resolution of high and low affinity states of the receptor by computer modeling of ligand-binding data. Molecular Pharmacology, 17, 14–23.Google ScholarPubMed
Hall, D. A. (2000) Modeling the functional effects of allosteric modulators at pharmacological receptors: An extension of the two-state model of receptor activation. Molecular Pharmacology, 58, 1412–1423.CrossRefGoogle ScholarPubMed
Weiss, J. M., Morgan, P. H., Lutz, M. W. & Kenakin, T. P. (1996a) The cubic ternary complex receptor-occupancy model. 1. Model description. Journal of Theoretical Biology, 178, 151–167.CrossRefGoogle Scholar
Weiss, J. M., Morgan, P. H., Lutz, M. W. & Kenakin, T. P. (1996b) The cubic ternary complex receptor-occupancy model. 2. Understanding apparent affinity. Journal of Theoretical Biology, 178, 169–182.CrossRefGoogle Scholar
Weiss, J. M., Morgan, P. H., Lutz, M. W. & Kenakin, T. P. (1996c) The cubic ternary complex receptor-occupancy model. 3. Resurrecting efficacy. Journal of Theoretical Biology, 181, 381–397.CrossRefGoogle Scholar
Christopoulos, A. & Kenakin, T. (2002) G protein-coupled receptor allosterism and complexing. Pharmacological Reviews, 54, 323–374.CrossRefGoogle ScholarPubMed
Leff, P., Scaramellini, C., Law, C. & Mckechnie, K. (1997) A three-state receptor model of agonist action. Trends in Pharmacological Sciences, 18, 355–362.CrossRefGoogle ScholarPubMed
Ehlert, F. J. (1988) Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods. Molecular Pharmacology, 33, 187–194.Google ScholarPubMed
Schwartz, T. W. & Holst, B. (2007) Allosteric enhancers, allosteric agonists and ago-allosteric modulators: Where do they bind and how do they act?Trends in Pharmacological Sciences, 28, 366–373.CrossRefGoogle ScholarPubMed
May, L. T., Leach, K., Sexton, P. M. & Christopoulos, A. (2007) Allosteric modulation of G protein-coupled receptors. Annual Review of Pharmacology and Toxicology, 47, 1–51.CrossRefGoogle ScholarPubMed
Conn, P. J., Christopoulos, A. & Lindsley, C. W. (2009) Allosteric modulators of GPCRs: A novel approach for the treatment of CNS disorders. Nature Reviews Drug Discovery, 8, 41–54.CrossRefGoogle ScholarPubMed
Bradley, M. E., Bond, M. E., Manini, J., Brown, Z. & Charlton, S. J. (2009) SB265610 is an allosteric, inverse agonist at the human cxcr2 receptor. British Journal of Pharmacology, 158, 328–338.CrossRefGoogle ScholarPubMed
Bettler, B., Kaupmann, K., Mosbacher, J. & Gassmann, M. (2004) Molecular structure and physiological functions of GABA(b) receptors. Physiological Reviews, 84, 835–867.CrossRefGoogle ScholarPubMed
Deriu, D., Gassmann, M., Firbank, S., Ristig, D., Lampert, C., Mosbacher, J., Froestl, W., Kaupmann, K., Bettler, B. & Grutter, M. G. (2005) Determination of the minimal functional ligand-binding domain of the GABA(b(1b)) receptor. Biochemical Journal, 386, 423–431.CrossRefGoogle Scholar
Pagano, A., Ruegg, D., Litschig, S., Stoehr, N., Stierlin, C., Heinrich, M., Floersheim, P., Prezeau, L., Carroll, F., Pin, J. P., Cambria, A., Vranesic, I., Flor, P. J., Gasparini, F. & Kuhn, R. (2000) The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan [b]chromen-1 alpha-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group 1 metabotropic glutamate receptors. Journal of Biological Chemistry, 275, 33750–33758.CrossRefGoogle Scholar
Binet, V., Goudet, C., Brajon, C., Corre, L., Acher, F., Pin, J. P. & Prezeau, L. (2004) Molecular mechanisms of GABA(b) receptor activation: New insights from the mechanism of action of CGP7930, a positive allosteric modulator. Biochemical Society Transactions, 32, 871–872.CrossRefGoogle ScholarPubMed
Dupuis, D. S., Relkovic, D., Lhuillier, L., Mosbacher, J. & Kaupmann, K. (2006) Point mutations in the transmembrane region of GABA(b2) facilitate activation by the positive modulator n,n ‘-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) in the absence of the GABA(b1) subunit. Molecular Pharmacology, 70, 2027–2036.CrossRefGoogle ScholarPubMed
Leach, K., Sexton, P. M. & Christopoulos, A. (2007) Allosteric GPCR modulators: Taking advantage of permissive receptor pharmacology. Trends in Pharmacological Sciences, 28, 382–389.CrossRefGoogle ScholarPubMed
Parmentier, M. L., Prezeau, L., Bockaert, J. & Pin, J. P. (2002) A model for the functioning of family 3 gpcrs. Trends in Pharmacological Sciences, 23, 268–274.CrossRefGoogle ScholarPubMed
Ott, D., Floersheim, P., Inderbitzin, W., Stoehr, N., Francotte, E., Lecis, G., Richert, P., Rihs, G., Flor, P. J., Kuhn, R. & Gasparini, F. (2000) Chiral resolution, pharmacological characterization, and receptor docking of the noncompetitive mglu1 receptor antagonist (+/-)-2-hydroxyimino-1a,2-dihydro-1h-7-oxacyclopropa[b]naphthalene-7a-ca rboxylic acid ethyl ester. Journal of Medicinal Chemistry, 43, 4428–4436.CrossRefGoogle Scholar
Avlani, V. A., Gregory, K. J., Morton, C. J., Parker, M. W., Sexton, P. M. & Christopoulos, A. (2007) Critical role for the second extracellular loop in the binding of both orthosteric and allosteric G protein-coupled receptor ligands. Journal of Biological Chemistry, 282, 25677–25686.CrossRefGoogle ScholarPubMed
Valant, C., Gregory, K. J., Hall, N. E., Scammells, P. J., Lew, M. J., Sexton, P. M. & Christopoulos, A. (2008) A novel mechanism of G protein-coupled receptor functional selectivity muscarinic partial agonist MCN-a-343 as a bitopic orthosteric/allosteric ligand. Journal of Biological Chemistry, 283, 29312–29321.CrossRefGoogle ScholarPubMed
Valant, C., Sexton, P. M. & Christopoulos, A. (2009) Orthosteric/allosteric bitopic ligands going hybrid at GPCRs. Molecular Interventions, 9, 125–135.CrossRefGoogle ScholarPubMed
Antony, J., Kellershohn, K., Mohr-Andra, M., Kebig, A., Prilla, S., Muth, M., Heller, E., Disingrini, T., Dallanoce, C., Bertoni, S., Schrobang, J., Trankle, C., Kostenis, E., Christopoulos, A., Holtje, H. D., Barocelli, E., Amici, M., Holzgrabe, U. & Mohr, K. (2009) Dualsteric GPCR targeting: A novel route to binding and signaling pathway selectivity. Faseb Journal, 23, 442–450.CrossRefGoogle ScholarPubMed
Lanzafame, A. A., Sexton, P. M. & Christopoulos, A. (2006) Interaction studies of multiple binding sites on m-4 muscarinic acetylcholine receptors. Molecular Pharmacology, 70, 736–746.CrossRefGoogle ScholarPubMed
Litschig, S., Gasparini, F., Rueegg, D., Stoehr, N., Flor, P. J., Vranesic, I., Prezeau, L., Pin, J. P., Thomsen, C. & Kuhn, R. (1999) CPCCOET, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Molecular Pharmacology, 55, 453–461.Google ScholarPubMed
Mitsukawa, K., Mombereau, C., Lotscher, E., Uzunov, D. P., Putten, H., Flor, P. J. & Cryan, J. F. (2006) Metabotropic glutamate receptor subtype 7 ablation causes dysregulation of the HPA axis and increases hippocampal BDNF protein levels: Implications for stress-related psychiatric disorders. Neuropsychopharmacology, 31, 1112–1122.CrossRefGoogle ScholarPubMed
Mitsukawa, K., Yamamoto, R., Ofner, S., Nozulak, J., Pescott, O., Lukic, S., Stoehr, N., Mombereau, C., Kuhn, R., Mcallister, K. H., Putten, H., Cryan, J. F. & Flor, P. J. (2005) A selective metabotropic glutamate receptor 7 agonist: Activation of receptor signaling via an allosteric site modulates stress parameters in vivo. Proceedings of the National Academy of Sciences of the United States of America, 102, 18712–18717.CrossRefGoogle ScholarPubMed
Urwyler, S., Mosbacher, J., Lingenhoehl, K., Heid, J., Hofstetter, K., Froestl, W., Bettler, B. & Kaupmann, K. (2001) Positive allosteric modulation of native and recombinant,gamma-aminobutyric acid(b) receptors by 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog cgp13501. Molecular Pharmacology, 60, 963–971.CrossRefGoogle ScholarPubMed
Urwyler, S., Pozza, M. F., Lingenhoehl, K., Mosbacher, J., Lampert, C., Froestl, W., Koller, M. & Kaupmann, K. (2003) N,n ‘-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds: Novel allosteric enhancers of gamma-aminobutyric acid(b) receptor function. Journal of Pharmacology and Experimental Therapeutics, 307, 322–330.CrossRefGoogle ScholarPubMed
Guery, S., Floersheim, P., Kaupmann, K. & Froestl, W. (2007) Syntheses and optimization of new GS39783 analogues as positive allosteric modulators of GABAb receptors. Bioorg. Med. Chem. Lett., 17, 6206–6211.CrossRefGoogle Scholar
Price, M. R., Baillie, G. L., Thomas, A., Stevenson, L. A., Easson, M., Goodwin, R., Mclean, A., Mcintosh, L., Goodwin, G., Walker, G., Westwood, P., Marrs, J., Thomson, F., Cowley, P., Christopoulos, A., Pertwee, R. G. & Ross, R. A. (2005) Allosteric modulation of the cannabinoid cb1 receptor. Molecular Pharmacology, 68, 1484–1495.CrossRefGoogle ScholarPubMed
Gjoni, T., Desrayaud, S., Imobersteg, S. & Urwyler, S. (2006) The positive allosteric modulator GS39783 enhances GABA(b) receptor-mediated inhibition of cyclic amp formation in rat striatum in vivo. Journal of Neurochemistry, 96, 1416–1422.CrossRefGoogle ScholarPubMed
Cryan, J. F., Kelly, P. H., Chaperon, F., Gentsch, C., Mombereau, C., Lingenhoehl, K., Froestl, W., Bettler, B., Kaupmann, K. & Spooren, W. (2004) Behavioral characterization of the novel GABA(b) receptor-positive modulator GS39783 (n,n ‘-dicyclopentyl-2methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-like activity without side effects associated with baclofen or benzodiazepines. Journal of Pharmacology and Experimental Therapeutics, 310, 952–963.CrossRefGoogle ScholarPubMed
Cryan, J. F. & Kaupmann, K. (2005) Don't worry ‘b’ happy!: A role for GABA(b) receptors in anxiety and depression. Trends in Pharmacological Sciences, 26, 36–43.CrossRefGoogle ScholarPubMed
Jacobson, L. H., Bettler, B., Kaupmann, K. & Cryan, J. F. (2006a) GABA(b(1)) receptor subunit isoforms exert a differential influence on baseline, but not GABA(b) receptor agonist-induced changes in mice. Journal of Pharmacology and Experimental Therapeutics, 319, 1317–1326.CrossRefGoogle Scholar
Jacobson, L. H., Kelly, P. H., Bettler, B., Kaupmann, K. & Cryan, J. F. (2006b) GABA(b(1)) receptor isoforms differentially mediate the acquisition and extinction of aversive taste memories. Journal of Neuroscience, 26, 8800–8803.CrossRefGoogle ScholarPubMed
Mombereau, C., Lhuillier, L., Kaupmann, K. & Cryan, J. F. (2007) GABA(b) receptor-positive modulation-induced blockade of the rewarding properties of nicotine is associated with a reduction in nucleus accumbens delta FOSb accumulation. Journal of Pharmacology and Experimental Therapeutics, 321, 172–177.CrossRefGoogle Scholar
Paterson, N. E., Vlachou, S., Guery, S., Kaupmann, K., Froestl, W. & Markou, A. (2008) Positive modulation of GABA(b) receptors decreased nicotine self-administration and counteracted nicotine-induced enhancement of brain reward function in rats. Journal of Pharmacology and Experimental Therapeutics, 326, 306–314.CrossRefGoogle ScholarPubMed
Maccioni, P., Carai, M. A. M., Kaupmann, K., Guery, S., Froestl, W., Leite-Morris, K. A., Gessa, G. L. & Colombo, G. (2009) Reduction of alcohol's reinforcing and motivational properties by the positive allosteric modulator of the GABA(b) receptor, BHF177, in alcohol-preferring rats. Alcoholism-Clinical and Experimental Research, 33, 1749–1756.CrossRefGoogle ScholarPubMed
Palucha, A., Klak, K., Branski, P., Putten, H., Flor, P. J. & Pilc, A. (2007) Activation of the mglu7 receptor elicits antidepressant-like effects in mice. Psychopharmacology, 194, 555–562.CrossRefGoogle ScholarPubMed
Fendt, M., Schmid, S., Thakker, D. R., Jacobson, L. H., Yamamoto, R., Mitsukawa, K., Maier, R., Natt, F., Husken, D., Kelly, P. H., Mcallister, K. H., Hoyer, D., Putten, H., Cryan, J. F. & Flor, P. J. (2008) mGlur7 facilitates extinction of aversive memories and controls amygdala plasticity. Molecular Psychiatry, 13, 970–979.CrossRefGoogle ScholarPubMed
Stachowicz, K., Branski, P., Klak, K., Putten, H., Cryan, J. F., Flor, P. J. & Pilc, A. (2008) Selective activation of metabotropic G-protein-coupled glutamate 7 receptor elicits anxiolytic-like effects in mice by modulating gabaergic neurotransmission. Behavioural Pharmacology, 19, 597–603.CrossRefGoogle ScholarPubMed
Chan, W. Y., Mckinzie, D. L., Bose, S., Mitchell, S. N., Witkin, J. M., Thompson, R. C., Christopoulos, A., Lazareno, S., Birdsall, N. J. M., Bymaster, F. P. & Felder, C. C. (2008) Allosteric modulation of the muscarinic m-4 receptor as an approach to treating schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 105, 10978–10983.CrossRefGoogle ScholarPubMed
Patil, S. T., Zhang, L., Martenyi, F., Lowe, S. L., Jackson, K. A., Andreev, B. V., Avedisova, A. S., Bardenstein, L. M., Gurovich, I. Y., Morozova, M. A., Mosolov, S. N., Neznanov, N. G., Reznik, A. M., Smulevich, A. B., Tochilov, V. A., Johnson, B. G., Monn, J. A. & Schoepp, D. D. (2007) Activation of mglu2/3 receptors as a new approach to treat schizophrenia: A randomized phase 2 clinical trial. Nature Medicine, 13, 1102–1107.CrossRefGoogle ScholarPubMed
Conn, P. J., Tamminga, C., Schoepp, D. D. & Lindsley, C. (2008) Schizophrenia: Moving beyond monoamine antagonists. Molecular Interventions, 8, 99–107.CrossRefGoogle ScholarPubMed
Varney, M. A., Cosford, N. D. P., Jachec, C., Rao, S. P., Sacaan, A., Lin, F. F., Bleicher, L., Santori, E. M., Flor, P. J., Allgeier, H., Gasparini, F., Kuhn, R., Hess, S. D., Velicelebi, G. & Johnson, E. C. (1999a) SIB-1757 and SIB-1893: Selective, noncompetitive antagonists of metabotropic glutamate receptor type 5. Journal of Pharmacology and Experimental Therapeutics, 290, 170–181.Google ScholarPubMed
Varney, M. A., Cosford, N., Jachec, C., Rao, S., Sacaan, A., Santori, E., Allgeier, H., Gasparini, F., Flor, P. J., Kuhn, R., Hess, S. D., Velicelebi, G. & Johnson, E. (1999b) Characterization of SIB-1757 and SIB-1893: Highly selective non-competitive antagonists of metabotropic glutamate receptor subtype 5 metabotropic (mglur5). Neuropharmacology, 38, 147.Google Scholar
Gasparini, F., Lingenhohl, K., Stoehr, N., Flor, P. J., Heinrich, M., Vranesic, I., Biollaz, M., Allgeier, H., Heckendorn, R., Urwyler, S., Varney, M. A., Johnson, E. C., Hess, S. D., Rao, S. P., Sacaan, A. I., Santori, E. M., Velicelebi, G. & Kuhn, R. (1999) 2-methyl-6- (phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mglu5 receptor antagonist. Neuropharmacology, 38, 1493–1503.CrossRefGoogle Scholar
Gasparini, F., Andres, H., Flor, P. J., Heinrich, M., Inderbitzin, W., Lingenhohl, K., Muller, H., Munk, V. C., Omilusik, K., Stierlin, C., Stoehr, N., Vranesic, I. & Kuhn, R. (2002) [H-3]-m-MPEP, a potent, subtype-selective radioligand for the metabotropic glutamate receptor subtype 5. Bioorg. Med. Chem. Lett., 12, 407–409.CrossRefGoogle Scholar
Hintermann, S., Vranesic, I., Allgeier, H., Brulisauer, A., Hoyer, D., Lemaire, M., Moenius, T., Urwyler, S., Whitebread, S., Gasparini, F. & Auberson, Y. P. (2007) ABP688, a novel selective and high affinity ligand for the labeling of mglu5 receptors: Identification, in vitro pharmacology, pharmacokinetic and biodistribution studies. Bioorganic & Medicinal Chemistry, 15, 903–914.CrossRefGoogle ScholarPubMed
Kuhn, R., Pagano, A., Stoehr, N., Vranesic, I., Flor, P. J., Lingenhohl, K., Spooren, W., Gentsch, C., Vassout, A., Pilc, A. & Gasparini, F. (2002) In vitro and in vivo characterization of MPEP, an allosteric modulator of the metabotropic glutamate receptor subtype 5: Review article. Amino Acids, 23, 207–211.CrossRefGoogle ScholarPubMed
O'Brien, J. A., Lemaire, W., Chen, T.-B., Chang, R. S. L., Jacobson, M. A., Ha, S. N., Lindsley, C. W., Schaffhauser, H. J., Sur, C., Pettibone, D. J., Conn, P. J. & Williams, D. L. (2003) A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. Molecular Pharmacology, 64, 731–740.CrossRefGoogle ScholarPubMed
Jaeschke, G., Wettstein, J. G., Nordquist, R. E. & Spooren, W. (2008) Mglu5 receptor antagonists and their therapeutic potential. Expert Opinion on Therapeutic Patents, 18, 123–142.CrossRefGoogle Scholar
Montana, M. C., Cavallone, L. F., Stubbert, K. K., Stefanescu, A. D., Kharasch, E. D. & Gereau, R. W. (2009) The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine. Journal of Pharmacology and Experimental Therapeutics, 330, 834–843.CrossRefGoogle ScholarPubMed
Berry-Kravis, E., Hessl, D., Coffey, S., Hervey, C., Schneider, A., Yuhas, J., Hutchison, J., Snape, M., Tranfaglia, M., Nguyen, D. V. & Hagerman, R. (2009) A pilot open label, single dose trial of fenobam in adults with fragile x syndrome. Journal of Medical Genetics, 46, 266–271.CrossRefGoogle ScholarPubMed
Harrington, P. E. & Fotsch, C. (2007) Calcium sensing receptor activators: Calcimimetics. Curr. Med. Chem., 14, 3027–3034.CrossRefGoogle ScholarPubMed
Dorr, P., Westby, M., Dobbs, S., Griffin, P., Irvine, B., Macartney, M., Mori, J., Rickett, G., Smith-Burchnell, C., Napier, C., Webster, R., Armour, D., Price, D., Stammen, B., Wood, A. & Perros, M. (2005) Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor ccr5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrobial Agents and Chemotherapy, 49, 4721–4732.CrossRefGoogle Scholar
Gjoni, T. & Urwyler, S. (2008) Receptor activation involving positive allosteric modulation, unlike full agonism, does not result in GABA(b) receptor desensitization. Neuropharmacology, 55, 1293–1299.CrossRefGoogle Scholar
Baker, J. G., Hall, I. P. & Hill, S. J. (2003) Agonist actions of “Beta-blockers” Provide evidence for two agonist activation sites or conformations of the human beta(1)-adrenoceptor. Molecular Pharmacology, 63, 1312–1321.CrossRefGoogle ScholarPubMed
Berg, K. A., Maayani, S., Goldfarb, J., Scaramellini, C., Leff, P. & Clarke, W. P. (1998) Effector pathway-dependent relative efficacy at serotonin type 2a and 2c receptors: Evidence for agonist-directed trafficking of receptor stimulus. Molecular Pharmacology, 54, 94–104.CrossRefGoogle ScholarPubMed
Gjoni, T. & Urwyler, S. (2009) Changes in the properties of allosteric and orthosteric GABA(b) receptor ligands after a continuous, desensitizing agonist pretreatment. European Journal of Pharmacology, 603, 37–41.CrossRefGoogle ScholarPubMed
Heitzler, D., Crépieux, P., Poupon, A., Clément, F., Fages, F. & Reiter, E. (2009) Towards a systems biology approach of g protein-coupled receptor signalling: Challenges and expectations. Comptes Rendus Biologies, 332, 947–957.CrossRefGoogle ScholarPubMed
Langmead, C. J. & Christopoulos, A. (2006) Allosteric agonists of 7TM receptors: Expanding the pharmacological toolbox. Trends in Pharmacological Sciences, 27, 475–481.CrossRefGoogle ScholarPubMed
Maj, M., Bruno, V., Dragic, Z., Yamamoto, R., Battaglia, G., Inderbitzin, W., Stoehr, N., Stein, T., Gasparini, F., Vranesic, I., Kuhn, R., Nicoletti, F. & Flor, P. J. (2003) (-)-PHCCC, a positive allosteric modulator of mglur4: Characterization, mechanism of action, and neuroprotection. Neuropharmacology, 45, 895–906.CrossRefGoogle ScholarPubMed
Miles, C. & Fiona, M. (2009) The impact of GPCR structures on pharmacology and structure-based drug design. British Journal of Pharmacology, 9999.Google Scholar
Rang, H. P. (2006) The receptor concept: Pharmacology's big idea. British Journal of Pharmacology, 147, S9-S16.CrossRefGoogle ScholarPubMed
Stephenson, R. P. (1956) Modification of receptor theory. British Journal of Pharmacology and Chemotherapy, 11, 379–393.CrossRefGoogle ScholarPubMed
Urwyler, S., Gjoni, T., Koljatic, J. & Dupuis, D. S. (2005) Mechanisms of allosteric modulation at GABA(b) receptors by CGP7930 and GS39783: Effects on affinities and efficacies of orthosteric ligands with distinct intrinsic properties. Neuropharmacology, 48, 343–353.CrossRefGoogle ScholarPubMed
Bokoch, M. P., Zou, Y. Z., Rasmussen, S. G. F., Liu, C. W., Nygaard, R., Rosenbaum, D. M., Fung, J. J., Choi, H. J., Thian, F. S., Kobilka, T. S., Puglisi, J. D., Weis, W. I., Pardo, L., Prosser, R. S., Mueller, L. & Kobilka, B. K. (2010) Ligand-specific regulation of the extracellular surface of a g-protein-coupled receptor. Nature, 463, 108–114.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×