Allosteric ligands interact with binding sites on the receptor molecule that are topographically distinct from the binding site for the endogenous agonist (the orthosteric site).
Allosteric modulators have at least three general advantages over standard orthosteric drugs:
First, there is a 'ceiling' to their effect; once the allosteric sites are completely occupied, no further allosteric effect is observed.
Second, they have the ability to selectively modify responses only in tissues in which the endogenous agonist is active.
Third, they offer the potential for greater subtype selectivity, owing to greater variation in allosteric sites relative to orthosteric sites, and/or different degrees of allosteric modulation at each receptor subtype.
Traditional radioligand binding assays, which use a radiolabelled 'probe' ligand to directly monitor occupancy of the orthosteric site on the receptor, are biased towards the detection of orthosteric effects. This could explain the current paucity of clinically available allosteric drugs.
As radioligand binding assays are inherently probe dependent, discovery programmes that are specifically aimed at identifying allosteric modulators using such assays should, if possible, use the endogenous orthosteric ligand as a probe. Radioligand concentrations might need to be optimized to maximize the chance of detecting allosteric effects, and additional validation assays to monitor radioligand dissociation rates are also useful.
Functional assays directly determine the desired physiological end point, and so are highly suitable for the detection of allosteric modulators. Potential disadvantages, such as a higher hit rate owing to activation of non-target receptors, could be offset by using radioligand binding as a secondary screen.
Cell-surface receptors are the targets for more than 60% of current drugs. Traditionally, optimizing the interaction of lead molecules with the binding site for the endogenous agonist (orthosteric site) has been viewed as the best means of achieving selectivity of action. However, recent developments have highlighted the fact that drugs can interact with binding sites on the receptor molecule that are distinct from the orthosteric site, known as allosteric sites. Allosteric modulators could offer several advantages over orthosteric ligands, including greater selectivity and saturability of their effect.
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Ehrlich, P. The Croonian Lecture: on immunity, with special reference to cell life. Proc. R. Soc. Lond. B 66, 424–448 (1900).
Langley, J. N. The Croonian Lecture — on nerve endings and excitable substances in cells. J. Physiol. (Lond.) 34, 170–194 (1906).
Drews, J. Drug discovery: a historical perspective. Science 287, 1960–1964 (2000).
Kenakin, T. Inverse, protean, and ligand-selective agonism: matters of receptor conformation. FASEB J. 15, 598–611 (2001).
Kenakin, T. P. Pharmacologic Analysis of Drug–Receptor Interaction (Lippincott-Raven, Philadelphia, 1997).
Frauenfelder, H., Parak, F. & Young, R. D. Conformational substates in proteins. Annu. Rev. Biophys. Biophys. Chem. 17, 451–479 (1988).
Frauenfelder, H., Sligar, S. G. & Wolynes, P. G. The energy landscapes and motions of proteins. Science 254, 1598–1603 (1991).
Frauenfelder, H. Proteins — paradigms of complex systems. Experientia 51, 200–203 (1995).
Colquhoun, D. Binding, gating, affinity and efficacy: the interpretation of structure–activity relationships for agonists and of the effects of mutating receptors. Br. J. Pharmacol. 125, 924–947 (1998).
Hall, D. A. Modeling the functional effects of allosteric modulators at pharmacological receptors: an extension of the two-state model of receptor activation. Mol. Pharmacol. 58, 1412–1423 (2000).
Christopoulos, A. & Kenakin, T. G protein-coupled receptor allosterism and complexing. Pharmacol. Rev. (in the press).
Ehlert, F. J., Roeske, W. R., Gee, K. W. & Yamamura, H. I. An allosteric model for benzodiazepine receptor function. Biochem. Pharmacol. 32, 2375–2383 (1983).
Ehlert, F. J. Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods. Mol. Pharmacol. 33, 187–194 (1988).A useful introduction to the theory that underlies the TCM for allosteric interactions.
Lazareno, S. & Birdsall, N. J. M. 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. Mol. Pharmacol. 48, 362–378 (1995).This paper describes rigorous methodology for the detection and analysis of allosteric interactions at GPCRs.
Lanzafame, A., Christopoulos, A. & Mitchelson, F. Interactions of agonists with an allosteric antagonist at muscarinic acetylcholine M2 receptors. Eur. J. Pharmacol. 316, 27–32 (1996).
Leppik, R. A., Lazareno, S., Mynett, A. & Birdsall, N. J. M. Characterization of the allosteric interactions between antagonists and amiloride analogues at the human α2A-adrenergic receptor. Mol. Pharmacol. 53, 916–925 (1998).
Ehlert, F. J. Gallamine allosterically antagonizes muscarinic receptor-mediated inhibition of adenylate cyclase activity in the rat myocardium. J. Pharmacol. Exp. Ther. 247, 596–602 (1988).
Christopoulos, A. in Current Protocols in Pharmacology (ed. Enna, S. J.) 1.22.1–1.22.40 (John Wiley & Sons, New York, 2000).
Birdsall, N. J. M. et al. Subtype-selective positive cooperative interactions between brucine analogs and acetylcholine at muscarinic receptors: functional studies. Mol. Pharmacol. 55, 778–786 (1999).
Birdsall, N. J. M., Lazareno, S. & Matsui, H. Allosteric regulation of muscarinic receptors. Prog. Brain Res. 109, 147–151 (1996).
Galzi, J.-L. & Changeux, J.-P. Neurotransmitter-gated ion channels as unconventional allosteric proteins. Curr. Opin. Struct. Biol. 4, 554–565 (1994).An analysis of the structural properties of allosteric sites across ligand-gated ion channels.
Smith, G. B. & Olsen, R. W. Functional domains of GABAA receptors. Trends Pharmacol. Sci. 16, 162–168 (1995).
Changeux, J. P. & Edelstein, S. J. Allosteric receptors after 30 years. Neuron 21, 959–980 (1998).A comprehensive overview of cell-surface receptor allosterism, with an emphasis on LGICs.
Costa, E. From GABAA receptor diversity emerges a unified vision of GABAergic inhibition. Annu. Rev. Pharmacol. Toxicol. 38, 321–350 (1998).
Rudolph, U. et al. Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes. Nature 401, 796–800 (1999).
Sigel, E. & Buhr, A. The benzodiazepine binding site of GABAA receptors. Trends Pharmacol. Sci. 18, 425–429 (1997).
Costa, E. & Guidotti, A. Benzodiazepines on trial: a research strategy for their rehabilitation. Trends Pharmacol. Sci. 17, 192–199 (1996).
Rudolph, U., Crestani, F. & Mohler, H. GABAA receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol. Sci. 22, 188–194 (2001).
Hebert, T. E. & Bouvier, M. Structural and functional aspects of G protein-coupled receptor oligomerization. Biochem. Cell Biol. 76, 1–10 (1998).
Devi, L. A. Heterodimerization of G-protein-coupled receptors: pharmacology, signaling and trafficking. Trends Pharmacol. Sci. 22, 532–537 (2001).
Matsui, H., Lazareno, S. & Birdsall, N. J. Probing of the location of the allosteric site on M1 muscarinic receptors by site-directed mutagenesis. Mol. Pharmacol. 47, 88–98 (1995).
Leppik, R. A., Miller, R. C., Eck, M. & Paquet, J. L. Role of acidic amino acids in the allosteric modulation by gallamine of antagonist binding at the M2 muscarinic acetylcholine receptor. Mol. Pharmacol. 45, 983–990 (1994).
Ellis, J. Allosteric binding sites on muscarinic receptors. Drug Dev. Res. 40, 193–204 (1997).
Gnagey, A. L., Seidenberg, M. & Ellis, J. Site-directed mutagenesis reveals two epitopes involved in the subtype selectivity of the allosteric interactions of gallamine at muscarinic acetylcholine receptors. Mol. Pharmacol. 56, 1245–1253 (1999).
Ellis, J. & Seidenberg, M. Interactions of alcuronium, TMB-8, and other allosteric ligands with muscarinic acetylcholine receptors: studies with chimeric receptors. Mol. Pharmacol. 58, 1451–1460 (2000).
Buller, S., Zlotos, D. P., Mohr, K. & Ellis, J. Allosteric site on muscarinic acetylcholine receptors: a single amino acid in transmembrane region 7 is critical to the subtype selectivities of caracurine V derivatives and alkane-bisammonium ligands. Mol. Pharmacol. 61, 160–168 (2002).
Pagano, A. et al. The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors. J. Biol. Chem. 275, 33750–33758 (2000).
Knoflach, F. et al. Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site. Proc Natl Acad Sci U S A 98, 13402–13407 (2001).
Christopoulos, A., Lanzafame, A. & Mitchelson, F. Allosteric interactions at muscarinic cholinoceptors. Clin. Exp. Pharmacol. Physiol. 25, 185–194 (1998).
Christopoulos, A., Sorman, J. L., Mitchelson, F. & El-Fakahany, E. E. Characterization of the subtype selectivity of the allosteric modulator heptane-1,7-bis-(dimethyl-3′-pthalimidopropyl) ammonium bromide (C7/3-phth) at cloned muscarinic acetylcholine receptors. Biochem. Pharmacol. 57, 171–179 (1999).
Lazareno, S., Gharagozloo, P., Kuonen, D., Popham, A. & Birdsall, N. J. M. Subtype-selective positive cooperative interactions between brucine analogues and acetylcholine at muscarinic recptors: radioligand binding studies. Mol. Pharmacol. 53, 573–589 (1998).
Gao, Z. & Ijzerman, A. P. Allosteric modulation of A2A adenosine receptors by amiloride analogues and sodium ions. Biochem. Pharmacol. 60, 669–676 (2000).
Urwyler, S. et al. Positive allosteric modulation of native and recombinant γ-aminobutyric acidB receptors by 2,6-di-tert-butyl-4-(3-hydroxy-2,2- dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501. Mol. Pharmacol. 60, 963–971 (2001).
Carroll, F. Y. et al. BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. Mol. Pharmacol. 59, 965–973 (2001).
Conigrave, A. D., Quinn, S. J. & Brown, E. M. Cooperative multi-modal sensing and therapeutic implications of the extracellular Ca2+-sensing receptor. Trends Pharmacol. Sci. 21, 401–407 (2000).
Kollias-Baker, C. et al. Allosteric enhancer PD 81,723 acts by novel mechanism to potentiate cardiac actions of adenosine. Circ. Res. 75, 961–971 (1994).
Christopoulos, A. & Mitchelson, F. Use of a spreadsheet to quantitate the equilibrium binding of an allosteric modulator. Eur. J. Pharmacol. 355, 103–111 (1998).
Kostenis, E. & Mohr, K. Composite action of allosteric modulators on ligand binding. Trends Pharmacol. Sci. 17, 443–444 (1996).
Christopoulos, A. in Current Protocols in Pharmacology (ed. Enna, S. J.) 1.21.1–1.21.45 (John Wiley & Sons, New York, 2000).A detailed step-by-step protocol for studying allosterism at G-protein-coupled receptors.
Litschig, S. et al. CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Mol. Pharmacol. 55, 453–461 (1999).
Thomas, E. A., Carson, M. J., Neal, M. J. & Sutcliffe, J. G. Unique allosteric regulation of 5-hydroxytryptamine receptor-mediated signal transduction by oleamide. Proc. Natl Acad. Sci. USA 94, 14115–14119 (1997).
Hedlund, P. B., Carson, M. J., Sutcliffe, J. G. & Thomas, E. A. Allosteric regulation by oleamide of the binding properties of 5-hydroxytryptamine7 receptors. Biochem. Pharmacol. 58, 1807–1813 (1999).
Lutz, M. & Kenakin, T. Quantitative Molecular Pharmacology and Informatics in Drug Discovery (John Wiley & Sons, New York, 1999).
Lazareno, S. in Receptor-Based Drug Design (ed. Leff, P.) 49–77 (Marcel Dekker, New York, 1998).
Arunlakshana, O. & Schild, H. O. Some quantitative uses of drug antagonists. Br. J. Pharmacol. 14, 48–57 (1959).
Kenakin, T. P. & Boselli, C. Pharmacologic discrimination between receptor heterogeneity and allosteric interaction: resultant analysis of gallamine and pirenzepine antagonism of muscarinic response in rat trachea. J. Pharmacol. Exp. Ther. 250, 944–952 (1989).
Christopoulos, A. & Mitchelson, F. Assessment of the allosteric interactions of the bisquaternary heptane-1,7-bis(dimethyl-3′-pthalimidopropyl)ammonium bromide at M1 and M2 muscarine receptors. Mol. Pharmacol. 46, 105–114 (1994).
Christopoulos, A. & Mitchelson, F. Application of an allosteric ternary complex model to the technique of pharmacological resultant analysis. J. Pharm. Pharmacol. 49, 781–786 (1997).
Nunnari, J. M., Repaske, M. G., Brandon, S., Cragoe, E. J. Jr & Limbird, L. E. Regulation of porcine brain α2-adrenergic receptors by Na+, H+ and inhibitors of Na+/H+ exchange. J. Biol. Chem. 262, 12387–12392 (1987).
Bruns, R. F. & Fergus, J. H. Allosteric enhancement of adenosine A1 receptor binding and function by 2-amino-3-benzoylthiophenes. Mol. Pharmacol. 38, 939–949 (1990).
Tränkle, C. & Mohr, K. Divergent modes of action among cationic allosteric modulators of muscarinic M2 receptors. Mol. Pharmacol. 51, 674–682 (1997).
Kostenis, E. & Mohr, K. Two-point kinetic experiments to quantify allosteric effects on radioligand dissociation. Trends Pharmacol. Sci. 17, 280–283 (1996).
Monod, J. & Jacob, F. General conclusions: teleonomic mechanisms in cellular metabolism, growth, and differentiation. Cold Spring Harb. Symp. Quant. Biol. 26, 389–401 (1961).
Monod, J., Changeux, J.-P. & Jacob, F. Allosteric proteins and cellular control systems. J. Mol. Biol. 6, 306–329 (1963).An introduction to the allosteric concept in enzymology.
Monod, J., Wyman, J. & Changeux, J.-P. On the nature of allosteric transitions: a plausible model. J. Mol. Biol. 12, 88–118 (1965).The first detailed allosteric model for oligomeric proteins.
Del Castillo, J. & Katz, B. Interaction at end-plate receptors between different choline derivatives. Proc. R. Soc. Lond. B 146, 369–381 (1957).
Katz, B. & Thesleff, S. A study of the 'desensitization' produced by acetylcholine at the motor end-plate. J. Physiol. (Lond.) 138, 63–80 (1957).
Colquhoun, D. in Drug Receptors (ed. Rang, H. P.) 149–182 (Macmillan, London, 1973).
Karlin, A. On the application of 'a plausible model' of allosteric proteins to the receptor for acetylcholine. J. Theor. Biol. 16, 306–320 (1967).
Thron, C. D. On the analysis of pharmacological experiments in terms of an allosteric receptor model. Mol. Pharmacol. 9, 1–9 (1973).
Leff, P. The two-state model of receptor activation. Trends Pharmacol. Sci. 16, 89–97 (1995).
Cuatrecasas, P. Membrane receptors. Annu. Rev. Biochem. 43, 169–214 (1974).
De Lean, A., Stadel, J. M. & Lefkowitz, R. J. A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled β-adrenergic receptor. J. Biol. Chem. 255, 7108–7117 (1980).The first application of the TCM to GPCRs.
Wregget, K. A. & De Lean, A. The ternary complex model. Its properties and application to ligand interactions with the D2-dopamine receptor of the anterior pituitary gland. Mol. Pharmacol. 26, 214–227 (1984).
Ehlert, F. J. The relationship between muscarinic receptor occupancy and adenylate cyclase inhibition in the rabbit myocardium. Mol. Pharmacol. 28, 410–421 (1985).
Stockton, J. M., Birdsall, N. J. M., Burgen, A. S. V. & Hulme, E. C. Modification of the binding properties of muscarinic receptors by gallamine. Mol. Pharmacol. 23, 551–557 (1983).
Lüllman, H., Ohnesorge, F. K., Schauwecker, G.-C. & Wasserman, O. Inhibition of the actions of carbachol and DFP on guinea pig isolated atria by alkane-bis-ammonium compounds. Eur. J. Pharmacol. 6, 241–247 (1969).
Clark, A. L. & Mitchelson, F. The inhibitory effects of gallamine on muscarinic receptors. Br. J. Pharmacol. 58, 323–331 (1976).
Costa, T. & Herz, A. Antagonists with negative intrinsic activity at δ-opioid receptors coupled to GTP-binding proteins. Proc. Natl Acad. Sci. USA 86, 7321–7325 (1989).
Samama, P., Cotecchia, S., Costa, T. & Lefkowitz, R. J. A mutation-induced activated state of the β2-adrenergic receptor. Extending the ternary complex model. J. Biol. Chem. 268, 4625–4636 (1993).
Weiss, J. M., Morgan, P. H., Lutz, M. W. & Kenakin, T. P. The cubic ternary complex receptor-occupancy model. I. Model description. J. Theor. Biol. 178, 151–167 (1996).
Jacoby, D. B., Gleich, G. J. & Fryer, A. D. Human eosinophil major basic protein is an endogenous allosteric antagonist at the inhibitory muscarinic M2 receptor. J. Clin. Invest. 91, 1314–1318 (1993).
Kumamoto, E. The pharmacology of amino-acid responses in septal neurons. Prog. Neurobiol. 52, 197–259 (1997).
Mennerick, S. et al. Effects on γ-aminobutyric acid (GABAA) receptors of a neuroactive steroid that negatively modulates glutamate neurotransmission and augments GABA neurotransmission. Mol. Pharmacol. 60, 732–741 (2001).
Rabow, L. E., Russek, S. J. & Farb, D. H. From ion currents to genomic analysis: recent advances in GABAA receptor research. Synapse 21, 189–274 (1995).
Belelli, I., Pistis, I., Peters, J. A. & Lambert, J. J. General anaesthetic action at transmitter-gated inhibitory amino acid receptors. Trends Pharmacol. Sci. 20, 496–502 (1999).
Gasior, M., Carter, R. B. & Witkin, J. M. Neuroactive steroids: potential therapeutic use in neurological and psychiatric disorders. Trends Pharmacol. Sci. 20, 107–112 (1999).
Ehlert, F. J., Roeske, W. R., Braestrup, C., Yamamura, S. H. & Yamamura, H. I. γ-Aminobutyric acid regulation of the benzodiazepine receptor: biochemical evidence for pharmacologically different effects of benzodiazepines and propyl β-carboline-3-carboxylate. Eur. J. Pharmacol. 70, 593–595 (1981).
Braestrup, C., Schmiechen, R., Neef, G., Nielsen, M. & Petersen, E. N. Interaction of convulsive ligands with benzodiazepine receptors. Science 216, 1241–1243 (1982).
Maelicke, A. & Albuquerque, E. X. New approach to drug therapy in Alzheimer's dementia. Drug Discov. Today 1, 53–59 (1996).
Albuquerque, E. X. et al. Properties of neuronal nicotinic acetylcholine recpeptors: pharmacological characterization and modulation of synaptic function. J. Pharmacol. Exp. Ther. 280, 1117–1136 (1997).
Bouzat, C. & Barrantes, F. J. Modulation of muscle nicotinic acetylcholine receptors by the glucocorticoid hydrocortisone. Possible allosteric mechanism of channel blockade. J. Biol. Chem. 271, 25835–25841 (1996).
Schrattenholz, A. et al. Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands. Mol. Pharmacol. 49, 1–6 (1996).
Changeux, J.-P. The TiPS Lecture. The nicotinic acetylcholine receptor: an allosteric protein prototype of ligand-gated ion channels. Trends Pharmacol. Sci. 11, 485–492 (1990).
Changeaux, J.-P. & Revah, F. The acetylcholine receptor molecule: allosteric sites and the ion channel. Trends Neurosci. 10, 245–249 (1987).
Pagan, O. R. et al. Cembranoid and long-chain alkanol sites on the nicotinic acetylcholine receptor and their allosteric interaction. Biochemistry 40, 11121–11130 (2001).
Krause, R. M. et al. Ivermectin: a positive allosteric effector of the α7 neuronal nicotinic acetylcholine receptor. Mol. Pharmacol. 53, 283–294 (1998).
Yamakura, T. & Shimoji, K. Subunit- and site-specific pharmacology of the NMDA receptor channel. Prog. Neurobiol. 59, 279–298 (1999).
Mothet, J. P. et al. d-Serine is an endogenous ligand for the glycine site of the N-methyl-d-aspartate receptor. Proc. Natl Acad. Sci. USA 97, 4926–4931 (2000).
Leeson, P. D. & Iversen, L. L. The glycine site on the NMDA receptor: structure–activity relationships and therapeutic potential. J. Med. Chem. 37, 4053–4067 (1994).
Marvizón, J.-C. & Baudry, M. Allosteric interactions and modulator requirement for NMDA receptor function. Eur. J. Pharmacol. Mol. Pharmacol. Sect. 269, 165–175 (1994).
Grimwood, S., Struthers, L. & Foster, A. C. Polyamines modulate [3H]L-689,560 binding to the glycine site of the NMDA receptor from rat brain. Eur. J. Pharmacol. Mol. Pharmacol. Sect. 266, 43–50 (1994).
Michel, A. D., Miller, K. J., Lundström, K., Buell, G. N. & Humphrey, P. P. A. Radiolabeling of the rat P2X4 purinoceptor: evidence for allosteric interactions of purinoceptor antagonists and monovalent cations with P2X purinoceptors. Mol. Pharmacol. 51, 524–532 (1997).
Bhattacharya, S. & Linden, J. The allosteric enhancer, PD 81,723, stabilizes human A1 adenosine receptor coupling to G proteins. Biochim. Biophys. Acta 1265, 15–21 (1995).
Kollias-Baker, C. A. et al. Agonist-independent effect of an allosteric enhancer of the A1 adenosine receptor in CHO cells stably expressing the recombinant human A1 receptor. J. Pharmacol. Exp. Ther. 281, 761–768 (1997).
Kourounakis, A., Visser, C., de Goote, M. & Ijzerman, A. P. Differential effects of the allosteric enhancer (2-amino-4,5-dimethyl-trienyl) [3-(trifluoromethyl) pheynl] methanone (PD81,723) on agonist and antagonist binding and function at the human wild-type and a mutant (T277A) adenosine A1 receptor. Biochem. Pharmacol. 61, 137–144 (2001).
Musser, B., Mudumbi, R. V., Liu, J., Olson, R. D. & Vestal, R. E. Adenosine A1 receptor-dependent and -independent effects of the allosteric enhancer PD81,723. J. Pharmacol. Exp. Ther. 288, 446–454 (1999).
Gao, Z. G. et al. Allosteric modulation of A3 adenosine receptors by a series of 3-(2-pyridinyl)isoquinoline derivatives. Mol. Pharmacol. 60, 1057–1063 (2001).
Leppik, R. A., Mynett, A., Lazareno, S. & Birdsall, N. J. M. Allosteric interactions between the antagonist prazosin and amiloride analogs at the human α1A-adrenergic receptor. Mol. Pharmacol. 57, 436–445 (2000).
Waugh, D. J., Gaivin, R. J., Damron, D. S., Murray, P. A. & Perez, D. M. Binding, partial agonism, and potentiation of α1-adrenergic receptor function by benzodiazepines: a potential site of allosteric modulation. J. Pharmacol. Exp. Ther. 291, 1164–1171 (1999).
Leppik, R. A. & Birdsall, N. J. Agonist binding and function at the human α2A-adrenoceptor: allosteric modulation by amilorides. Mol. Pharmacol. 58, 1091–1099 (2000).
Wilson, A. L., Seibert, K., Brandon, S., Cragoe, E. J. Jr & Limbird, L. E. Monovalent cation and amiloride analog modulation of adrenergic ligand binding to the unglycosylated α2B-adrenergic receptor subtype. Mol. Pharmacol. 39, 481–486 (1991).
Molderings, G. J., Menzel, S., Kathmann, M., Schlicker, E. & Gothert, M. Dual interaction of agmatine with the rat α2D-adrenoceptor: competitive antagonism and allosteric activation. Br. J. Pharmacol. 130, 1706–1712 (2000).
Swaminath, G., Steenhuis, J., Kobilka, B. & Lee, T. W. Allosteric modulation of β2-adrenergic receptor by Zn2+. Mol. Pharmacol. 61, 65–72 (2002).
Hammerland, L. G., Garrett, J. E., Hung, B. C., Levinthal, C. & Nemeth, E. F. Allosteric activation of the Ca2+ receptor expressed in Xenopus laevis oocytes by NPS 467 or NPS 568. Mol. Pharmacol. 53, 1083–1088 (1998).
Conigrave, A. D., Quinn, S. J. & Brown, E. M. l-Amino acid sensing by the extracellular Ca2+-sensing receptor. Proc. Natl Acad. Sci. USA 97, 4814–4819 (2000).
Cox, M. A. et al. Human interferon-inducible 10-kDa protein and human interferon-inducible T cell-α chemoattractant are allotopic ligands for human CXCR3: differential binding to receptor states. Mol. Pharmacol. 59, 707–715 (2001).
Zhao, J. et al. Anti-HIV agent trichosanthin enhances the capabilities of chemokines to stimulate chemotaxis and G protein activation, and this is mediated through interaction of trichosanthin and chemokine receptors. J. Exp. Med. 190, 101–111 (1999).
Sabroe, I. et al. A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J. Biol. Chem. 275, 25985–25992 (2000).
Schetz, J. A. & Sibley, D. R. Zinc allosterically modulates antagonist binding to cloned D1 and D2 dopamine recpetors. J. Neurochem. 68, 1990–1997 (1997).
Hoare, S. R. J. & Strange, P. G. Regulation of D2 dopamine receptors by amiloride and amiloride analogs. Mol. Pharmacol. 50, 1295–1308 (1996).
Schetz, J. A., Chu, A. & Sibley, D. R. Zinc modulates antagonist interactions with D2-like dopamine receptors through distinct molecular mechanisms. J. Pharmacol. Exp. Ther. 289, 956–964 (1999).
Blandin, V., Vigne, P., Breittmayer, J. P. & Frelin, C. Allosteric inhibition of endothelin ETA receptors by 3,5-dibromosalicylic acid. Mol. Pharmacol. 58, 1461–1469 (2000).
Talbodec, A. et al. Aspirin and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism. Mol. Pharmacol. 57, 797–804 (2000).
Spooren, W. P., Gasparini, F., Salt, T. E. & Kuhn, R. Novel allosteric antagonists shed light on mGlu5 receptors and CNS disorders. Trends Pharmacol. Sci. 22, 331–337 (2001).
Proska, J. & Tucek, S. Mechanisms of steric and cooperative actions of alcuronium on cardiac muscarinic acetylcholine receptors. Mol. Pharmacol. 45, 709–717 (1994).
Knaus, G. A., Knaus, H. G. & Saria, A. Complex allosteric interaction of heparin with neurokinin-1 receptors. Eur. J. Pharmacol. 207, 267–270 (1991).
Spedding, M., Sweetman, A. J. & Weetman, D. F. Antagonism of adenosine 5′-triphosphate-induced relaxation by 2-2′-pyridylisatogen in the taenia of guinea-pig caecum. Br. J. Pharmacol. 53, 575–583 (1975).
King, B. F. et al. Potentiation by 2,2′-pyridylisatogen tosylate of ATP-responses at a recombinant P2Y1 purinoceptor. Br. J. Pharmacol. 117, 1111–1118 (1996).
Fillion, G. et al. A new peptide, 5-HT-moduline, isolated and purified from mammalian brain specifically interacts with 5-HT1B/1D receptors. Behav. Brain Res. 73, 313–317 (1996).
Massot, O. et al. Molecular, cellular and physiological characteristics of 5-HT-moduline, a novel endogenous modulator of 5–HT1B receptor subtype. Ann. NY Acad. Sci. 861, 174–182 (1998).
A.C. is grateful to F. Mitchelson and M. J. Lew for critical review of the manuscript. Work in A.C.'s laboratory is funded by grants from the National Health and Medical Research Council of Australia and by Amrad Australia. A.C. is a C. R. Roper Research Fellow of the Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Australia.
- ORTHOSTERIC SITE
The endogenous agonist binding site on a receptor. This domain is also recognized by classic competitive antagonists and inverse agonists.
- ALLOSTERIC SITE
A modulatory binding site on a receptor that is topographically distinct from the agonist binding site.
- ALLOSTERIC INTERACTION
An interaction between two topographically distinct binding sites on the same receptor complex.
- ALLOSTERIC TRANSITION
The isomerization of a receptor protein between multiple conformational states.
- COOPERATIVE BINDING
The binding of two or more molecules of the same ligand to a receptor complex. Sometimes used in a less strict sense to describe the concomitant binding of more than one molecule of any chemical type to a receptor complex.
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Christopoulos, A. Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat Rev Drug Discov 1, 198–210 (2002). https://doi.org/10.1038/nrd746
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