G PROTEIN‐COUPLED RECEPTORS

Abstract

Overview: The completion of the Human Genome Project allowed the identification of a large family of proteins with a common motif of seven groups of 20–24 hydrophobic amino acids arranged as α-helices. Approximately 800 of these seven transmembrane (7TM) receptors have been identified of which over 300 are non-olfactory receptors (see Fredriksson et al., 2003; Lagerstrom and Schioth, 2008). Subdivision on the basis of sequence homology allows the definition of rhodopsin, secretin, adhesion, glutamate and Frizzled receptor families. NC-IUPHAR recognizes Classes A, B, and C, which equate to the rhodopsin, secretin, and glutamate receptor families. The nomenclature of 7TM receptors is commonly used interchangeably with G protein-coupled receptors (GPCR), although the former nomenclature recognises signalling of 7TM receptors through pathways not involving G proteins. For example, adiponectin and membrane progestin receptors have some sequence homology to 7TM receptors but signal independently of G proteins and appear to reside in membranes in an inverted fashion compared to conventional GPCR. Additionally, the NPR-C natriuretic peptide receptor (see Page S195) has a single transmembrane domain structure, but appears to couple to G proteins to generate cellular responses. The 300+ non-olfactory GPCR are the targets for the majority of drugs in clinical usage (Overington et al., 2006), although only a minority of these receptors are exploited therapeutically. Signalling through GPCR is enacted by the activation of heterotrimeric GTP-binding proteins (G proteins), made up of α, β and γ subunits, where the α and βγ subunits are responsible for signalling. The α subunit (tabulated below) allows definition of one series of signalling cascades and permits grouping of GPCRs to suggest common cellular, tissue and behavioural responses. Gβγ subunits (tabulated below) also are able to signal, in a manner independent of the Gα subunits. Recently, the concept of agonist bias, or functional selectivity, has arisen (see Kenakin and Miller, 2010), which suggests that particular agonists, or allosteric modulators, may be able to promote post-receptor signalling through one cascade at the expense of an alternative. This has complicated the scenario for classification of GPCR. For the purposes of the Guide to Receptors and Channels, ‘Principal transduction’ is limited to the predominant established Gα signalling. Gαs family:β1-adrenoceptors (see Page S26) in the heart couple principally through Gαs to activate adenylyl cyclase activity (see Page S288) and elevate intracellular cyclic AMP levels. This in turn leads to activation of protein kinase A (see Page S310) and the consequent phosphorylation and enhancement of function of voltage-gated calcium channels (Cav1.2, see Page S142). This, in turn leads to the observed action of noradrenaline (norepinephrine) or adrenaline (epinephrine) in increasing cardiac rate and force of contraction. The identification of other Gs-coupled GPCR in the heart would allow prediction of a similar effect on heart rate and force through the same mechanisms. In other tissues, Gs-coupled receptors would be predicted to evoke smooth muscle relaxation (e.g. β2-adrenoceptors in bronchioles, Page S26), enhance secretion (e.g. H2 histamine receptors in gastric parietal cells, Page S70), stimulate lipolysis in adipocytes (e.g. β3-adrenoceptors, Page S26) and inhibit platelet aggregation (e.g. IP prostanoid receptors, Page S97). Gαi family: M2 muscarinic acetylcholine receptors (see Page S20) in the heart couple via Gαi subunits to inhibit adenylyl cyclase activity (see Page S288). Vagal innervation targets these receptors, primarily in the atria, to counteract the effects of noradrenaline and adrenaline in the cardiac myocyte, leading to a reduction in heart rate and force of contraction. In addition, Gαi subunits and Gβγ subunits (see below) enhance potassium channel opening (KiR2.x, see Page S158). The ensuing hyperpolarization of the cardiac myocyte leads to a reduction in voltage-gated L-type calcium channel activity and a consequent inhibition of rate and force of cardiac contraction – the manifestation of vagal nerve stimulation. In other tissues, Gi-coupled receptors would be predicted to inhibit neurotransmitter release (e.g. µ opioid receptors, Page S88, on parasympathetic nerve terminals in the small intestine), inhibit lipolysis in adipocytes (e.g. A1 adenosine receptors, Page S22) and enhance platelet aggregation (e.g. P2Y12 receptors, Page S91). In the retina, transducin (αt) subunits allow coupling to a cyclic GMP-specific phosphodiesterase, PDE6 (see Page S290). This reduces cellular cyclic GMP levels leading to a reduction of currents through cyclic nucleotide-gated channels (CNG, Page S153) and subsequent decrease of the ‘dark’ current. Gαq family: M3 muscarinic acetylcholine receptors (see Page S20) in bronchial smooth muscle couple via Gαq/11 subunits to stimulate phospholipase C-β activity (see Page S302). This leads to an elevation of intracellular calcium ions through inositol 1,4,5-trisphosphate action at IP3 receptors (see Page S157), activation of protein kinase C (see Page S311) and the consequent smooth muscle contraction and reduced airway conductance. In other tissues, Gq-coupled receptor activation leads to increased platelet aggregation (e.g. P2Y1 receptors, Page S91). Lysophosphatidic acid receptors (see Page S76) and proteinase-activated receptors (see Page S95) are examples of GPCR which couple through multiple G protein families, including Gα12/13 leading to activation of a guanine nucleotide exchange factor, or GEF, for the Rho family of low molecular GTP-binding proteins (ENSFM00500000269651), the subsequent activation of Rho kinase (see Page S313) and regulation of the cytoskeleton, leading to cellular shape changes and/or migration. GNAQP1 is a pseudogene (ENSG00000214077). Gβγ subunits: although β and γ subunits are synthesised as separate entities, they are considered to generate a complex which is essentially biologically irreversible. Acylation and prenylation ensure an association with the plasma membrane, where Gβγ subunits may regulate ion channel activities, or recruit members of the G protein-coupled receptor kinase family, also known as β-adrenoceptor kinases (see Page S310). Phosphorylation of particular cytoplasmic serine/threonine residues of GPCR allows binding of β-arrestin (ENSFM00250000000572). These proteins act as scaffolding partners facilitating internalization of GPCR as a mechanism of desensitization, or coupling to alternative signalling pathways (e.g. MAP kinases, see Page S312). GNB1L (ENSG00000185838) and GNB2L1 (ENSG00000204628) are described as Gβ-like proteins on the basis of sequence homology. Four Gγ pseudogenes are defined in the human genome (GNG5P1, ENSG00000213536; GNG5P2, ENSG00000133136; GNG5P3, ENSG00000254949; GNG5P5, ENSG00000234590). Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP et al. (2005). International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev57: 279–288. Fredholm BB, Hokfelt T, Milligan G (2007). G-protein-coupled receptors: an update. Acta Physiol190: 3–7. Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB (2003). The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol63: 1256–1272. Hill SJ, Williams C, May LT (2010). Insights into GPCR pharmacology from the measurement of changes in intracellular cyclic AMP; advantages and pitfalls of differing methodologies. Br J Pharmacol161: 1266–1275. Kenakin T (2010). Being mindful of seven-transmembrane receptor ‘guests’ when assessing agonist selectivity. Br J Pharmacol160: 1045–1047. Kenakin T, Miller LJ (2010). Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol Rev62: 265–304. Kenakin TP (2009). Cellular assays as portals to seven-transmembrane receptor-based drug discovery. Nat Rev Drug Discov8: 617–626. Lagerstrom MC, Schioth HB (2008). Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov7: 339–357. Milligan G (2009). G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function. Br J Pharmacol158: 5–14. Overington JP, Al-Lazikani B, Hopkins AL (2006). How many drug targets are there? Nat Rev Drug Discov5: 993–996. http://www.iuphar-db.org/ While the remainder of this section focuses on those GPCR for which there is substantial pharmacological information, or interest, listed below are a number of putative GPCR identified by IUPHAR (Foord et al., 2005), for which only preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. The GPCR in the table below are all Class A, rhodopsin-like GPCR. In the set of tables below, putative GPCR with as-yet unidentified endogenous ligands are listed. Adhesion GPCRs: Adhesion GPCRs are structurally identified on the basis of a large extracellular region, similar to the Class B GPCR, but which is linked to the 7TM region by a ‘stalk’ motif containing a GPCR proteolytic site. The N-terminus often shares structural homology with proteins such as lectins and immunoglobulins, leading to the term adhesion GPCR (see Fredriksson et al., 2003; Yona et al., 2008). Whilst the taste of acid and salty foods appears to be sensed by regulation of ion channel activity, bitter, sweet and umami tastes are sensed by specialised GPCR. Two classes of taste GPCR have been identified, T1R and T2R, which are similar in sequence and structure to Class C and Class A GPCR, respectively. Activation of taste receptors appears to involve gustducin (Gαt3, see Page S6) and Gα14-mediated signalling, although the precise mechanisms remain obscure. Gene disruption studies suggest the involvement of PLCβ2 (Zhang et al., 2003), TRPM5 (Zhang et al., 2003) and IP3 (Hisatsune et al., 2007) receptors in post-receptor signalling of taste receptors. Although predominantly associated with the oral cavity, taste receptors are also located elsewhere, including further down the gastrointestinal system, in the lungs and in the brain. Sweet/Umami: T1R3 acts as an obligate partner in T1R1/T1R3 and T1R2/T1R3 heterodimers, which sense umami or sweet, respectively. T1R1/T1R3 heterodimers respond to L-glutamate and may be positively allosterically modulated by 5′-nucleoside monophosphates, such as GMP (Li et al., 2002). T1R2/T1R3 heterodimers respond to sugars, such as sucrose, and artificial sweeteners, such as saccharin (Nelson et al., 2001). Bitter: the composition and stoichiometry of bitter taste receptors is not yet established. Bitter receptors appear to separate into two groups, with very restricted ligand specificity or much broader responsiveness. For example, T2R5 responded to cycloheximide, but not 10 other bitter compounds (Chandrashekar et al., 2000), while T2R14 responded to at least eight different bitter tastants, including (-)-α-thujone and picrotoxinin (Behrens et al., 2004). Andres-Barquin PJ, Conte C (2004). Molecular basis of bitter taste: the T2R family of G protein-coupled receptors. Cell Biochem Biophys41: 99–112. Bachmanov AA, Beauchamp GK (2007). Taste receptor genes. Annu Rev Nutr27: 389–414. DeSimone JA, Lyall V (2006). Taste receptors in the gastrointestinal tract III. Salty and sour taste: sensing of sodium and protons by the tongue. Am J Physiol Gastrointest Liver Physiol291: G1005–G1010. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP et al. (2005). International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev57: 279–288. Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB (2003). The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol63: 1256–1272. Kinnamon SC (2011). Taste receptor signaling – from tongues to lungs. Acta Physiol (Oxf) in press. Lagerstrom MC, Schioth HB (2008). Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov7: 339–357. Meyerhof W (2005). Elucidation of mammalian bitter taste. Rev Physiol Biochem Pharmacol154: 37–72. Overington JP, Al-Lazikani B, Hopkins AL (2006). How many drug targets are there? Nat Rev Drug Discov5: 993–996. Renwick AG, Molinary SV (2010). Sweet-taste receptors, low-energy sweeteners, glucose absorption and insulin release. Br J Nutr104: 1415–1420. Rozengurt E (2006). Taste receptors in the gastrointestinal tract. I. Bitter taste receptors and α-gustducin in the mammalian gut. Am J Physiol Gastrointest Liver Physiol291: G171–G177. Rozengurt E, Sternini C (2007). Taste receptor signaling in the mammalian gut. Curr Opin Pharmacol7: 557–562. Temussi PA (2009). Sweet, bitter and umami receptors: a complex relationship. Trends Biochem Sci34: 296–302. Tepper BJ (2008). Nutritional implications of genetic taste variation: the role of PROP sensitivity and other taste phenotypes. Annu Rev Nutr28: 367–388. Yarmolinsky DA, Zuker CS, Ryba NJ (2009). Common sense about taste: from mammals to insects. Cell139: 234–244. Yona S, Lin HH, Siu WO, Gordon S, Stacey M (2008). Adhesion-GPCRs: emerging roles for novel receptors. Trends Biochem Sci33: 491–500. 5-HT receptors [nomenclature as agreed by NC-IUPHAR Subcommittee on 5-HT receptors (Hoyer et al., 1994) and subsequently revised (Hartig et al., 1996)] are, with the exception of the ionotropic 5-HT3 class, GPCR where the endogenous agonist is 5-HT. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT2A (non-functional), 5-HT2C (non-functional), 5-HT4, 5-HT6 (non-functional) and 5-HT7 receptors. Unique amongst the GPCRs, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11and also pharmacology (reviewed by Bockaert et al., 2006; Werry et al., 2008). Most 5-HT receptors (except 5-ht1e and 5-ht5a/5b) play specific roles mediating functional responses in different tissues (reviewed by Villalón and Centurión, 2007; Ramage and Villalón, 2008). Tabulated pKi and KD values refer to binding to human 5-HT receptors unless indicated otherwise. Unreferenced values are extracted from the NC-IUPHAR database (http://www.iuphar-db.org). The nomenclature of 5-HT1B/5-HT1D receptors has been revised (Hartig et al., 1996). Only the non-rodent form of the receptor was previously called 5-HT1Dβ. The human 5-HT1B receptor (tabulated) displays a different pharmacology to the rodent forms of the receptor due to Thr335 of the human sequence being replaced by Asn in rodent receptors. NAS181 is a selective antagonist of the rodent 5-HT1B receptor. Fananserin and ketanserin bind with high affinity to dopamine D4 and histamine H1 receptors respectively, and ketanserin is a potent α1 adrenoceptor antagonist, in addition to blocking 5-HT2A receptors. The human 5-ht5A receptor has been claimed to couple to several signal transduction pathways when stably expressed in C6 glioma cells (Noda et al., 2003). The human orthologue of the mouse 5-ht5b receptor is non-functional due to interruption of the gene by stop codons. The 5-ht1e receptor appears not to have been cloned from mouse, or rat, impeding definition of its function. In addition to the receptors listed in the table, an ‘orphan’ receptor, unofficially termed 5-HT1P, has been described (Gershon, 1999). Abbreviations: 5-CT, 5-carboxamidotryptamine; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; [N-methyl-3H3]AZ10419369, 5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylicacid (4-morpholin-4-yl-phenyl)-amide; BIMU8, (endo-N-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide hydrochloride; BRL15572, 3-[4-(3-chlorophenyl) piperazin-1-yl]-1,1,-diphenyl-2-propanol; BRL54443, 5-hydroxy-3-(1-methylpiperidin-4-yl)-1H-indole; BW723C86, 1-[5(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine hydrochloride; CP94253: 3- (1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3, 2-b] pyridine; E6801, 6-chloro-N-(3-(2-dimethylamino)ethyl)-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide; E55888, dimethyl-{2-[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-amine; EGIS-7625, 1-benzyl-4-[(2-nitro-4-methyl-5-amino)-phenyl]-piperazine; F13640, 3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyperidin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]-methanone ; F15599, 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone; FR260010, (N-[3-(4-methyl-1H-imidazol-1-yl)phenyl]-5,6-dihydrobenzo[h]quinazolin-4-amine; GR55562, 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide; GR113808, [1-2[(methylsuphonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate; GR125743, n-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-3-methyl-4-(4-pyrindinyl)benzamide; GTI, 5-hydroxytryptamine-5-O-carboxymethylglycyltyrosinamide; L694247, 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indol-3yl] ethanamine; LY334370, 5-(4-flurobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate; LY344864, N-[(6R) -6-dimethylamino-6,7,8,9-tetrahydro-5H-carbazo-3-yl]-4- fluorobenzamide; LY573144, 2,4,6-trifluoro-N-[6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2yl]benzamide; MDL100907, (+/-)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol]; NAD299, (R)-3-N,N-dicyclobutylamino-8-fluoro-[6-3H]-3,4-dihydro-2H-1-benzo pyran-5-carboxamide; NAS181, (R)-(+)-2-[[[3-(morpholinomethyl)-2H-chromen-8-yl]oxy]methyl] morpholine methane sulfonate; p-[18F]MPPF 4-(2′-methoxyphenyl)-1-[2′-(N-2″-pyridinyl)-p-fluorobenzamido]-ethyl piperazine; PNU109291, (S)-3,4-dihydro-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methyl-1H-2-benzopyran-6-carboximide; RP62203, 2-[3-(4-(4-fluorophenyl)-piperazinyl)propyl]naphto[1,8-ca]isothiazole-1,1-dioxide; Ro600175, (S)-2-(6-chloro-5-fluroindol-1-yl)-1-methyethylamine; Ro630563, 4-amino-N-[2,6-bis(methylamino)pyridin-4-yl]benzenesulphonamide; RS57639, 4-amino-5-chloro-2-methoxy benzoic acid 1-(3-[2,3-dihydrobenzo[1,4]dioxin-6yl)-propyl]-piperidin-4yl methyl ester; RS67506, 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(2-methyl sulphonylamino)ethyl-4-piperidinyl]-1-propanone hydrochloride; RS100235, 1-(8-amino-7-chloro-1,4-benzodioxan-5-yl)-5-((3-(3,4-dimethoxyphenyl)prop-1-yl)piperidin-4-yl)propan-1-one; RS102221, 8-[5-(5-amino 2,4-dimethoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione; RS127445, (2-amino-4-(4-fluoronaphthyl-1-yl)-6-isopropylpyrimidine); SB204070, 1-butyl-4-piperidinylmethyl-8-amino-7-chloro-1-4-benzoioxan-5-carboxylate; SB207710, 1-butyl-4-piperidinylmethyl-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate; SB224289,1′-methyl-5[[2′-methyl-4′-)5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4′-piperidine]oxalate; SB236057,1′-ethyl-5-(2′-methyl-4′ (5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indol3-3,4′-piperidine; SB242084, 6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl] indoline; SB258585, 4-iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulphonamide; SB258719, (R)-3,N-dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzene sulphonamide; SB269970, (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulphonyl)phenol; SB271046, 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulphonamide; SB357134, N-(2,5-dibromo-3-flurophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulphonamide; SB-399885, N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide; SB656104, 6-((R)-2-[2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl]-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride; SB699551, 3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4′-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride; SB714786, 2-methyl-5-({2-[4-(8-quinolinylmethyl)-1-piperazinyl]ethyl}oxy)quinoline; UH301, 5-fluoro-8-hydroxy-2-(dipropylamino) tetralin; U92016A, (+)-R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole; WAY100635, N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohexanecarboxamide trichloride, WAY163909, (7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole; WAY-181187, 2-[1-(6-chloroimidazo[2,1-b]thiazol-5-ylsulfonyl)-1H-indol-3-yl]ethylamine Aloyo VJ, Berg KA, Spampinato U, Clarke WP, Harvey JA (2009). 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In addition to the agents listed in the table, AC-42, its structural analogues AC-260584 and 77-LH-28-1, desmethylclozapine, TBPB and LuAE51090 have been described as functionally selective agonists of the M1 receptor subtype via binding in a mode distinct from that utilized by non-selective agonists (Spalding et al., 2002, 2006; Sur et al., 2003; Langmead et al., 2006, 2008; May et al., 2007; Jones et al., 2008; Lebon et al., 2009; Avlani et al., 2010; Sams et al., 2010). There are two pharmacologically characterised allosteric sites on muscarinic receptors, one defined by it binding gallamine, strychnine and brucine, and the other binds KT5720, WIN62,577, WIN51,708 and staurosporine (Lazareno et al., 2000, 2002). There are selective enhancers of acetylcholine binding and action; brucine, BQCA, KT5720, VU0090157, VU0029767 and ML169 (VU0405652) at M1 receptors, PG135 at M2 receptors, N-chloromethylbrucine and WIN62,577 at M3 receptors and thiochrome, LY2033298, VU0152099 and VU0152100 at M4 receptors, and VU0238429 at M5 receptors (Birdsall and Lazareno, 2005; Brady et al., 2008; Chan et al., 2008; Shirey et al., 2008; Bridges et al., 2009; Ma et al., 2009, Marlo et al., 2009; Reid et al., 2011). LY2033298 has also been shown to activate the M4 receptor directly via an allosteric site (Nawaratne et al., 2008; 2010; Leach et al., 2010; 2011). The allosteric site for gallamine and strychnine on M2 receptors can be labelled by [3H]dimethyl-W84 (Tränkle et al., 2003). McN-A-343 is a functionally selective partial agonist that appears to interact in a bitopic mode with both the orthosteric and an allosteric site on the M2 muscarinic receptor (Valant et al., 2008). THRX-160209, hybrid 1 and hybrid 2, are multivalent (bitopic) ligands that also achieve selectivity for M2 receptors by binding both to the orthosteric and a nearby allosteric site (Steinfeld et al., 2007; Antony et al., 2009). VU0255035 is a recently described competitive orthosteric antagonist with selectivity for the M1 receptor (Sheffler et al., 2009), and LY593093 has recently been described as a selective orthosteric partial agonist of the M1 receptor (Watt et al., 2011). Antagonist data tabulated are pKi values determined for human recombinant receptors. MT3 (m4-toxin) and MT7 (m1-toxin1) are toxins contained with the venom of the Eastern green mamba (Dendroaspis augusticeps) (see Potter et al., 2004; Servent and Fruchart-Gaillard, 2009). Abbreviations: 77-LH-28-1, 1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone; AC-42, 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine hydrogen chloride; AC-260584, 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one; AFDX116 (otenzepad), 1-[2-[2-(diethylaminomethyl)piperidin-1-yl]acetyl]-5H-pyrido[2,3-b][1,4]benozodiazepin-6-one; AFDX384, (±)-5,11-dihydro-11-([(2-[2-[dipropylamino)methyl]-1-piperidinyl)ethyl)amino)carbonyl)-6H-pyrido[2,3-b](1,4)benzodiazepine-6-one; BQCA, benzyl quinolone carboxylic acid; Butylthio-TZTP, butylthio-thiadiazolyltetrahydro-1-methyl-pyridine; Dimethyl-W84, N,N'-bis[3-(1,3-dihydro-1,3-dioxo-4-methyl-2H-isoindol-2-yl)propyl]-N,N,N',N'-tetramethyl-1,6-hexanediaminium diiodide; FP-TZTP, [3-(3-(3-Fluoropropyl)thio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine; 4-DAMP, 4-diphenylacetoxy-N-methylpiperidine methiodide; Hybrid 1, 2-{3-[1-(6-{1,1-dimethyl-1-[4-(isoxazol-3-yloxy)but-2-ynyl]-ammonium}hexyl)-1,1 dimethylammonio]propyl}isoindoline-1,3-dione dibromide; Hybrid 2, 2-{3-[1-(6-{1,1-dimethyl-1-[4-(isoxazol-3-yloxy)but-2-ynyl]-ammonium}hexyl)-1,1-dimethylammonio]-2,2-d