{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:25:06Z","timestamp":1787016306480,"version":"build-2736575974"},"reference-count":38,"publisher":"Elsevier BV","issue":"3","license":[{"start":{"date-parts":[[2004,3,1]],"date-time":"2004-03-01T00:00:00Z","timestamp":1078099200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2004,3,1]],"date-time":"2004-03-01T00:00:00Z","timestamp":1078099200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["jpet.aspetjournals.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pharmacology and Experimental Therapeutics"],"published-print":{"date-parts":[[2004,3]]},"DOI":"10.1124\/jpet.103.059840","type":"journal-article","created":{"date-parts":[[2004,2,25]],"date-time":"2004-02-25T17:12:55Z","timestamp":1077729175000},"page":"1062-1072","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":51,"title":["Application of a Kinetic Model to the Apparently Complex Behavior of Negative and Positive Allosteric Modulators of Muscarinic Acetylcholine Receptors"],"prefix":"10.1016","volume":"308","author":[{"given":"Vimesh","family":"Avlani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren T.","family":"May","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick M.","family":"Sexton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Christopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1124\/jpet.103.059840_bib1","doi-asserted-by":"crossref","unstructured":"Birdsall NJ, Lazareno S, and Matsui H (1996) Allosteric regulation of muscarinic receptors. Prog Brain Res 109: 147-151.","DOI":"10.1016\/S0079-6123(08)62096-8"},{"key":"10.1124\/jpet.103.059840_bib2","doi-asserted-by":"crossref","unstructured":"Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248-254.","DOI":"10.1006\/abio.1976.9999"},{"key":"10.1124\/jpet.103.059840_bib3","doi-asserted-by":"crossref","unstructured":"Bruns RF and Fergus JH (1990) Allosteric enhancement of adenosine A1 receptor binding and function by 2-amino-3-benzoylthiophenes. Mol Pharmacol 38: 939-949.","DOI":"10.1016\/S0026-895X(25)09591-4"},{"key":"10.1124\/jpet.103.059840_bib4","doi-asserted-by":"crossref","unstructured":"Buller S, Zlotos DP, Mohr K, and Ellis J (2002) 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.","DOI":"10.1124\/mol.61.1.160"},{"key":"10.1124\/jpet.103.059840_bib5","unstructured":"Burnham KP and Anderson DR (2002) Model Selection and Inference, A Practical Information-Theoretic Approach, 2nd ed., Springer, New York."},{"key":"10.1124\/jpet.103.059840_bib6","doi-asserted-by":"crossref","unstructured":"Christopoulos A (1998) Assessing the distribution of parameters in models of ligand-receptor interaction: to log or not to log. Trends Pharmacol Sci 19: 351-357.","DOI":"10.1016\/S0165-6147(98)01240-1"},{"key":"10.1124\/jpet.103.059840_bib7","doi-asserted-by":"crossref","unstructured":"Christopoulos A (2000) Quantification of allosteric interactions at G protein-coupled receptors using radioligand binding assays, in Current Protocols in Pharmacology (Enna SJ ed), pp 1.22.21-1.22.40. Wiley & Sons, New York.","DOI":"10.1002\/0471141755.ph0122s11"},{"key":"10.1124\/jpet.103.059840_bib8","doi-asserted-by":"crossref","unstructured":"Christopoulos A (2002) Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat Rev Drug Discov 1: 198-210.","DOI":"10.1038\/nrd746"},{"key":"10.1124\/jpet.103.059840_bib9","doi-asserted-by":"crossref","unstructured":"Christopoulos A and El-Fakahany EE (1999) Qualitative and quantitative assessment of relative agonist efficacy. Biochem Pharmacol 58: 735-748.","DOI":"10.1016\/S0006-2952(99)00087-8"},{"key":"10.1124\/jpet.103.059840_bib10","doi-asserted-by":"crossref","unstructured":"Christopoulos A and Kenakin T (2002) G protein-coupled receptor allosterism and complexing. Pharmacol Rev 54: 323-374.","DOI":"10.1124\/pr.54.2.323"},{"key":"10.1124\/jpet.103.059840_bib11","doi-asserted-by":"crossref","unstructured":"Christopoulos and Lew (2000) Beyond eyeballing: fitting models to experimental data in biomedical applications of computer modeling (Christopoulos A ed) pp 195-231, CRC Press, Boca Raton, FL.","DOI":"10.1201\/9781420041873.ch7"},{"key":"10.1124\/jpet.103.059840_bib12","doi-asserted-by":"crossref","unstructured":"Christopoulos A, Lanzafame A, and Mitchelson F (1998) Allosteric interactions at muscarinic cholinoceptors. Clin Exp Pharmacol Physiol 25: 184-194.","DOI":"10.1111\/j.1440-1681.1998.t01-4-.x"},{"key":"10.1124\/jpet.103.059840_bib13","doi-asserted-by":"crossref","unstructured":"De Lean A, Stadel JM, and Lefkowitz RJ (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled \u03b2-adrenergic receptor. J Biol Chem 255: 7108-7117.","DOI":"10.1016\/S0021-9258(20)79672-9"},{"key":"10.1124\/jpet.103.059840_bib14","doi-asserted-by":"crossref","unstructured":"Drews J (2000) Drug discovery: a historical perspective. Science (Wash DC) 287: 1960-1964.","DOI":"10.1126\/science.287.5460.1960"},{"key":"10.1124\/jpet.103.059840_bib15","doi-asserted-by":"crossref","unstructured":"Ehlert FJ (1985) The relationship between muscarinic receptor occupancy and adenylate cyclase inhibition in the rabbit myocardium. Mol Pharmacol 28: 410-421.","DOI":"10.1016\/S0026-895X(25)14182-5"},{"key":"10.1124\/jpet.103.059840_bib16","doi-asserted-by":"crossref","unstructured":"Ehlert FJ (1988) Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods. Mol Pharmacol 33: 187-194.","DOI":"10.1016\/S0026-895X(25)13145-3"},{"key":"10.1124\/jpet.103.059840_bib17","doi-asserted-by":"crossref","unstructured":"Ellis J (1997) Allosteric binding sites on muscarinic receptors. Drug Dev Res 40: 193-204.","DOI":"10.1002\/(SICI)1098-2299(199702)40:2<193::AID-DDR9>3.3.CO;2-8"},{"key":"10.1124\/jpet.103.059840_bib18","doi-asserted-by":"crossref","unstructured":"Felder CC, Bymaster FP, Ward J, and DeLapp N (2000) Therapeutic opportunities for muscarinic receptors in the central nervous system. J Med Chem 43: 4333-4353.","DOI":"10.1021\/jm990607u"},{"key":"10.1124\/jpet.103.059840_bib19","doi-asserted-by":"crossref","unstructured":"Holzgrabe U and Mohr K (1998) Allosteric modulators of ligand binding to muscarinic acetylcholine receptors. Drug Disc Today 3: 214-222.","DOI":"10.1016\/S1359-6446(97)01161-6"},{"key":"10.1124\/jpet.103.059840_bib20","doi-asserted-by":"crossref","unstructured":"Im WB, Chio CL, Alberts GL, and Dinh DM (2003) Positive allosteric modulator of the human 5-HT2C receptor. Mol Pharmacol 64: 78-84.","DOI":"10.1124\/mol.64.1.78"},{"key":"10.1124\/jpet.103.059840_bib21","doi-asserted-by":"crossref","unstructured":"Insel PA, Mahan LC, Motulsky HJ, Stoolman LM, and Koachman AM (1983) Time-dependent decreases in binding affinity of agonists for \u03b2-adrenergic receptors of intact S49 lymphoma cells. J Biol Chem 258: 13597-13605.","DOI":"10.1016\/S0021-9258(17)43957-3"},{"key":"10.1124\/jpet.103.059840_bib22","doi-asserted-by":"crossref","unstructured":"Jakub\u00edk J, Bac\u00e1kov\u00e1 L, El-Fakahany EE, and Tucek S (1995) Subtype selectivity of the positive allosteric action of alcuronium at cloned M1-M5 muscarinic acetylcholine receptors. J Pharmacol Exp Ther 274: 1077-1083.","DOI":"10.1016\/S0022-3565(25)10553-3"},{"key":"10.1124\/jpet.103.059840_bib23","unstructured":"Kenakin TP (1997) Pharmacologic Analysis of Drug-Receptor Interaction, 3rd ed. Lippincott-Raven, Philadelphia, PA."},{"key":"10.1124\/jpet.103.059840_bib24","doi-asserted-by":"crossref","unstructured":"Kostenis E and Mohr K (1996) Two-point kinetic experiments to quantify allosteric effects on radioligand dissociation. Trends Pharmacol Sci 17: 280-283.","DOI":"10.1016\/0165-6147(96)10034-1"},{"key":"10.1124\/jpet.103.059840_bib25","doi-asserted-by":"crossref","unstructured":"Lazareno S and Birdsall NJM (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. Mol Pharmacol 48: 362-378.","DOI":"10.1016\/S0026-895X(25)10255-1"},{"key":"10.1124\/jpet.103.059840_bib26","doi-asserted-by":"crossref","unstructured":"Lazareno S, Popham A, and Birdsall NJ (2002) Analogs of WIN 62, 577 define a second allosteric site on muscarinic receptors. Mol Pharmacol 62: 1492-1505.","DOI":"10.1124\/mol.62.6.1492"},{"key":"10.1124\/jpet.103.059840_bib27","doi-asserted-by":"crossref","unstructured":"Lee NH and El-Fakahany EE (1991) Allosteric antagonists of the muscarinic acetylcholine receptor. Biochem Pharmacol 42: 199-205.","DOI":"10.1016\/0006-2952(91)90703-8"},{"key":"10.1124\/jpet.103.059840_bib28","doi-asserted-by":"crossref","unstructured":"Motulsky H and Christopoulos A (2003) Fitting Models to Biological Data Using Linear and Nonlinear Regression. GraphPad Software, Inc., San Diego, CA.","DOI":"10.1093\/oso\/9780195171792.001.0001"},{"key":"10.1124\/jpet.103.059840_bib29","unstructured":"Press WH, Teukolsky SA, Vetterling WT, and Flannery BP (1992) Numerical Recipes in C. The Art of Scientific Computing. Cambridge University Press, Cambridge, MA."},{"key":"10.1124\/jpet.103.059840_bib30","doi-asserted-by":"crossref","unstructured":"Proska J and Tu\u010dek S (1994) Mechanisms of steric and cooperative actions of alcuronium on cardiac muscarinic acetylcholine receptors. Mol Pharmacol 45: 709-717.","DOI":"10.1016\/S0026-895X(25)10157-0"},{"key":"10.1124\/jpet.103.059840_bib31","doi-asserted-by":"crossref","unstructured":"Stockton JM, Birdsall NJM, Burgen ASV, and Hulme EC (1983) Modification of the binding properties of muscarinic receptors by gallamine. Mol Pharmacol 23: 551-557.","DOI":"10.1016\/S0026-895X(25)14327-7"},{"key":"10.1124\/jpet.103.059840_bib32","doi-asserted-by":"crossref","unstructured":"Toews ML and Perkins JP (1984) Agonist-induced changes in \u03b2-adrenergic receptors on intact cells. J Biol Chem 259: 2227-2235.","DOI":"10.1016\/S0021-9258(17)43342-4"},{"key":"10.1124\/jpet.103.059840_bib33","doi-asserted-by":"crossref","unstructured":"Toews ML, Kendall Harden T, and Perkins JP (1983) High-affinity binding of agonists to \u03b2-adrenergic receptors on intact cells. Proc Natl Acad Sci USA 80: 3553-3557.","DOI":"10.1073\/pnas.80.12.3553"},{"key":"10.1124\/jpet.103.059840_bib34","doi-asserted-by":"crossref","unstructured":"Tr\u00e4nkle C, Weyand O, Voigtlander U, Birdsall NJ, Mohr K, Mynett A, and Lazareno S (2003) Interactions of orthosteric and allosteric ligands with [3H]dimethyl-W84 at the common allosteric site of muscarinic M2 receptors. Mol Pharmacol 64: 180-190.","DOI":"10.1124\/mol.64.1.180"},{"key":"10.1124\/jpet.103.059840_bib35","doi-asserted-by":"crossref","unstructured":"Tu\u010dek S and Proska J (1995) Allosteric modulation of muscarinic acetylcholine receptors. Trends Pharmacol Sci 16: 205-212.","DOI":"10.1016\/S0165-6147(00)89023-9"},{"key":"10.1124\/jpet.103.059840_bib36","doi-asserted-by":"crossref","unstructured":"Tu\u010dek S, Musilkova J, Nedoma J, Proska J, Shelkvnikov S, and Vorlicek J (1990) Positive cooperativity in the binding of alcuronium and N-methylscopolamine to muscarinic acetylcholine receptors. Mol Pharmacol 38: 674-680.","DOI":"10.1016\/S0026-895X(25)09526-4"},{"key":"10.1124\/jpet.103.059840_bib37","doi-asserted-by":"crossref","unstructured":"Waelbroeck M (1994) Identification of drugs competing with d-tubocurarine for an allosteric site on cardiac muscarinic receptors. Mol Pharmacol 46: 685-692.","DOI":"10.1016\/S0026-895X(25)09800-1"},{"key":"10.1124\/jpet.103.059840_bib38","doi-asserted-by":"crossref","unstructured":"Wregget KA and Wells JW (1995) Cooperativity manifest in the binding properties of purified cardiac muscarinic receptors. J Biol Chem 270: 22488-22499.","DOI":"10.1074\/jbc.270.38.22488"}],"container-title":["The Journal of Pharmacology and Experimental Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022356524312212?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022356524312212?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1124\/jpet.103.059840","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T15:48:17Z","timestamp":1739980097000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0022356524312212"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,3]]},"references-count":38,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2004,3]]}},"alternative-id":["S0022356524312212"],"URL":"https:\/\/doi.org\/10.1124\/jpet.103.059840","relation":{},"ISSN":["0022-3565"],"issn-type":[{"value":"0022-3565","type":"print"}],"subject":[],"published":{"date-parts":[[2004,3]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Application of a Kinetic Model to the Apparently Complex Behavior of Negative and Positive Allosteric Modulators of Muscarinic Acetylcholine Receptors","name":"articletitle","label":"Article Title"},{"value":"The Journal of Pharmacology and Experimental Therapeutics","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1124\/jpet.103.059840","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2004 The American Society for Pharmacology and Experimental Therapeutics","name":"copyright","label":"Copyright"}]}}