Therapeutic Targets Database
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TTD Target ID: TTDS00004

Target Information
NameMuscarinic acetylcholine receptor M3    
Type of targetSuccessful target    
SynonymsM3 receptor    
DiseaseAirway hyperreactivity[1]
Urge incontinence
[ICD9: 787.6, 788.3   ICD10: N39.3-N39.4, R15, R32]
[2]
Drug(s)CevimelineApprovedSj?gren's syndrome[3]
DarifenacinApprovedUrinary incontinence[4]
Diphemanil MethylsulfateApprovedPeptic ulcer disease[5]
OxybutyninApprovedUrinary and bladder difficulties[6]
SolifenacinApprovedOveractive bladder[7]
SuccinylcholineApprovedSpasms, Pain[8][9]
TiotropiumApprovedChronic obstructive pulmonary disease[10]
TolterodineApprovedUrinary incontinence[11][12]
LAS-34273Phase III completedChronic obstructive pulmonary disease[13]
RevatropateDiscontinued in Phase IChronic obstructive pulmonary disease[13]
BioChemical ClassG-protein coupled receptor (rhodopsin family)    
PathwayCalcium signaling pathway
Neuroactive ligand-receptor interaction
Regulation of actin cytoskeleton
UniProt IDP20309
PDB Structure2CSA.    
FunctionThe muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins.    
SequenceMTLHNNSTTSPLFPNISSSWIHSPSDAGLPPGTVTHFGSYNVSRAAGNFSSPDGTTDDPL GGHTVWQVVFIAFLTGILALVTIIGNILVIVSFKVNKQLKTVNNYFLLSLACADLIIGVI SMNLFTTYIIMNRWALGNLACDLWLAIDYVASNASVMNLLVISFDRYFSITRPLTYRAKR TTKRAGVMIGLAWVISFVLWAPAILFWQYFVGKRTVPPGECFIQFLSEPTITFGTAIAAF YMPVTIMTILYWRIYKETEKRTKELAGLQASGTEAETENFVHPTGSSRSCSSYELQQQSM KRSNRRKYGRCHFWFTTKSWKPSSEQMDQDHSSSDSWNNNDAAASLENSASSDEEDIGSE TRAIYSIVLKLPGHSTILNSTKLPSSDNLQVPEEELGMVDLERKADKLQAQKSVDDGGSF PKSFSKLPIQLESAVDTAKTSDVNSSVGKSTATLPLSFKEATLAKRFALKTRSQITKRKR MSLVKEKKAAQTLSAILLAFIITWTPYNIMVLVNTFCDSCIPKTFWNLGYWLCYINSTVN PVCYALCNKTFRTTFKMLLLCQCDKKKRRKQQYQQRQSVIFHKRAPEQAL
Related US Patent6,500,822
6,627,644
6,635,658
6,645,958
6,667,301
Target ValidationClick to Find Target Validation Information.    
QSAR ModelClick to Find Target QSAR Model.    
Inhibitor1'-Benzyl-3-phenyl-[3,4']bipiperidinyl-2,6-dione[14]
1,1-diphenyl-2- (3-tropanyl)ethanol[15]
1-Methyl-1- (4-pyrrolidin-1-yl-but-2-ynyl)-urea[16]
2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]decan-3-one[17]
2-Methyl-6-pyrrolidin-1-yl-hex-4-ynal oxime[18]
3- (3-benzylamino)-piperidin-2-one[19]
3-Methyl-7-pyrrolidin-1-yl-hept-5-yn-2-one[18]
3-Tetrazol-2-yl-1-aza-bicyclo[2.2.2]octane[20]
4- (4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one[21]
6-Dimethylamino-2-methyl-hex-4-ynal oxime[18]
7-Dimethylamino-3-methyl-hept-5-yn-2-one[18]
7-Dimethylamino-hept-5-yn-2-one[18]
7-Dimethylamino-hept-5-yn-2-one oxime[18]
7-Pyrrolidin-1-yl-hept-5-yn-2-one[18]
7-Pyrrolidin-1-yl-hept-5-yn-2-one oxime[18]
A-987306[22]
ACECLIDINE[23]
Acetic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester[24]
BRL-55473[25]
Benzoic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester[26]
CREMASTRINE[27]
FLUMEZAPINE[28]
FM1-10[29]
FM1-43[29]
GNF-PF-5618[30]
ISOCLOZAPINE[31]
ISOLOXAPINE[32]
N- (4-Dimethylamino-but-2-ynyl)-N-methyl-acetamide[18]
N-DESMETHYLCLOZAPINE[21]
N-methoxyquinuclidine-3-carboximidoyl chloride[25]
N-methoxyquinuclidine-3-carboximidoyl fluoride[25]
NOCARDIMICIN A[30]
Nocardimicin F[30]
Noccardimicin E[30]
Propionic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester[26]
SULFOARECOLINE[33]
Tiotropium Bromide[34]
UCB-101333-3[35]
XANOMELINE[36]
nocardimicin C[30]
nocardimicin D[30]
AgonistCevimeline[3]
Antagonist3- (1-carbamoyl-1,1-diphenylmethyl)-1-[11]
4-DAMP[37][38]
Darifenacin[4]
Diphemanil Methylsulfate[5]
LAS-34273[13]
Olterodine[2]
Oxybutynin[6]
Oxybutynine[39]
PTAC[2]
Revatropate[13]
Solifenacin[7]
Succinylcholine[8][9]
Tiotropium[10]
Tolterodine[11][12]
Zamifenacin[40]
MultitargetRevatropate[13]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Selective muscarinic receptor antagonists for airway diseases. Curr Opin Pharmacol. 2001 Jun;1(3):223-9. To Reference
Ref 2Which muscarinic receptor is important in the bladder? World J Urol. 2001 Nov;19(5):299-306. To Reference
Ref 3Degradation of submandibular gland AQP5 by parasympathetic denervation of chorda tympani and its recovery by cevimeline, an M3 muscarinic receptor agonist. Am J Physiol Gastrointest Liver Physiol. 2008 Jul;295(1):G112-G123. Epub 2008 May 1. To Reference
Ref 4M(1) and M(3) muscarinic receptors are involved in the release of urinary bladder-derived relaxant factor. Pharmacol Res. 2009 May;59(5):300-5. Epub 2009 Feb 5. To Reference
Ref 5LC determination of diphemanil methylsulfate: application to stability study of stored pharmaceutical formulations. J Pharm Biomed Anal. 2002 Jun 1;28(5):811-8. To Reference
Ref 6Transdermal oxybutynin. Drugs. 2009;69(3):327-37. doi: 10.2165/00003495-200969030-00008. To Reference
Ref 7Comparison of muscarinic receptor selectivity of solifenacin and oxybutynin in the bladder and submandibular gland of muscarinic receptor knockout mice. Eur J Pharmacol. 2009 Aug 1;615(1-3):201-6. Epub 2009 May 13. To Reference
Ref 8The involvement of histaminic and muscarinic receptors in the bronchoconstriction induced by myorelaxant administration in sensitized rabbits. Anesth Analg. 2008 Dec;107(6):1899-906. To Reference
Ref 9Anesthesiology. 1998 Mar;88(3):744-50.Neuromuscular relaxants as antagonists for M2 and M3 muscarinic receptors. To Reference
Ref 10DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. To Reference
Ref 11Signal transduction underlying carbachol-induced contraction of human urinary bladder. J Pharmacol Exp Ther. 2004 Jun;309(3):1148-53. Epub 2004 Feb 9. To Reference
Ref 12Nat Rev Drug Discov. 2003 Jan;2(1):38-51.Knockouts model the 100 best-selling drugs--will they model the next 100? To Reference
Ref 13Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91. To Reference
Ref 14J Med Chem. 1989 May;32(5):1057-62.Synthesis and biological evaluation of [125I]- and [123I]-4-iododexetimide, a potent muscarinic cholinergic receptor antagonist. To Reference
Ref 15Bioorg Med Chem Lett. 2009 Aug 15;19(16):4560-2. Epub 2009 Jul 8.Discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide as an efficacious inhaled muscarinic acetylcholine receptor antagonist for the treatment of COPD. To Reference
Ref 16J Med Chem. 1992 Aug 21;35(17):3270-9.Urea and 2-imidazolidone derivatives of the muscarinic agents oxotremorine and N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide. To Reference
Ref 17J Med Chem. 1998 Oct 22;41(22):4181-5.Synthesis and modeling studies of a potent conformationally rigid muscarinic agonist: 1-azabicyclo[2.2.1]heptanespirofuranone. To Reference
Ref 18Bioorg. Med. Chem. Lett. 2(8):803-808 (1992) To Reference
Ref 19J Med Chem. 2007 Apr 19;50(8):1925-32. Epub 2007 Mar 17.Designing active template molecules by combining computational de novo design and human chemist's expertise. To Reference
Ref 20J Med Chem. 1992 Apr 3;35(7):1280-90.Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives. To Reference
Ref 21J Med Chem. 2010 Sep 9;53(17):6386-97.Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential. To Reference
Ref 22J Med Chem. 2008 Nov 27;51(22):7094-8.cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia. To Reference
Ref 23J Med Chem. 1993 Apr 2;36(7):842-7.Design, synthesis, and neurochemical evaluation of 5-(3-alkyl-1,2,4- oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidines as M1 muscarinic receptor agonists. To Reference
Ref 24J Med Chem. 1998 Jun 4;41(12):2047-55.6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors. To Reference
Ref 25Bioorg. Med. Chem. Lett. 2(8):791-796 (1992) To Reference
Ref 26J Med Chem. 2000 Jun 29;43(13):2514-22.6beta-Acyloxy(nor)tropanes: affinities for antagonist/agonist binding sites on transfected and native muscarinic receptors. To Reference
Ref 27J Nat Prod. 2005 Apr;68(4):572-3.Cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata. To Reference
Ref 28J Med Chem. 1989 Dec;32(12):2573-82.Synthesis and pharmacological evaluation of a series of 4-piperazinylpyrazolo[3,4-b]- and -[4,3-b][1,5]benzodiazepines as potential anxiolytics. To Reference
Ref 29Bioorg Med Chem Lett. 2008 Jan 15;18(2):825-7. Epub 2007 Nov 17.Design and synthesis of a fluorescent muscarinic antagonist. To Reference
Ref 30J Nat Prod. 2005 Jul;68(7):1061-5.Nocardimicins A, B, C, D, E, and F, siderophores with muscarinic M3 receptor inhibiting activity from Nocardia sp. TP-A0674. To Reference
Ref 31J Med Chem. 1990 Feb;33(2):809-14.Chloro-substituted, sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents. To Reference
Ref 32J Med Chem. 1981 Sep;24(9):1021-6.Synthesis of clozapine analogues and their affinity for clozapine and spiroperidol binding sites in rat brain. To Reference
Ref 33J Med Chem. 1988 Jul;31(7):1312-6.Heterocyclic muscarinic agonists. Synthesis and biological activity of some bicyclic sulfonium arecoline bioisosteres. To Reference
Ref 34J Med Chem. 2009 Aug 27;52(16):5076-92.Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide). To Reference
Ref 35Bioorg Med Chem Lett. 2007 Jun 1;17(11):3077-80. Epub 2007 Mar 19.Dual M3 antagonists-PDE4 inhibitors. Part 2: Synthesis and SAR of 3-substituted azetidinyl derivatives. To Reference
Ref 36Bioorg. Med. Chem. Lett. 2(8):809-814 (1992) To Reference
Ref 37An increase in intracelluar free calcium ions modulated by cholinergic receptors in rat facial nucleus. Chin Med J (Engl). 2009 May 5;122(9):1049-55. To Reference
Ref 38The effects of the antagonists of muscarinic acetylcholine receptor subtypes in rat brain on urinary bladder contraction. Nippon Hinyokika Gakkai Zasshi. 2002 Mar;93(3):427-34. To Reference
Ref 39Generation of an agonistic binding site for blockers of the M(3) muscarinic acetylcholine receptor. Biochem J. 2008 May 15;412(1):103-12. To Reference
Ref 40Drug treatment options for irritable bowel syndrome: managing for success. Drugs Aging. 2001;18(3):201-11. To Reference



 

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