TTD Target ID: TTDS00003

Target Information
Name	Muscarinic acetylcholine receptor M2
Type of target	Successful target
Synonyms	M2 receptor
Disease	Alzheimer's disease    [1]
	Analgesics    [2]
	Autoimmune cardiomyopathy    [3]
	Bronchoconstriction (cold air-induced)    [4]
	Chronic obstructive pulmonary disease, unspecified    [4]
	Hypothermia    [5]
	Neurogenic bladder    [6]
	Pain, unspecified    [2]
	Tremor, unspecified    [5]
Drug(s)	Gallamine Triethiodide		Approved	Stabilize muscle contractions	[7]
	Methylscopolamine		Approved	Peptic ulcer disease	[8]
	Scopolamine		Approved	Nausea and Addiction	[9][10]
BioChemical Class	G-protein coupled receptor (rhodopsin family)
Pathway	Calcium signaling pathway
	Neuroactive ligand-receptor interaction
	Regulation of actin cytoskeleton
UniProt ID	P08172
PDB Structure	1LUB.
Function	The 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.
Sequence	MNNSTNSSNNSLALTSPYKTFEVVFIVLVAGSLSLVTIIGNILVMVSIKVNRHLQTVNNY FLFSLACADLIIGVFSMNLYTLYTVIGYWPLGPVVCDLWLALDYVVSNASVMNLLIISFD RYFCVTKPLTYPVKRTTKMAGMMIAAAWVLSFILWAPAILFWQFIVGVRTVEDGECYIQF FSNAAVTFGTAIAAFYLPVIIMTVLYWHISRASKSRIKKDKKEPVANQDPVSPSLVQGRI VKPNNNNMPSSDDGLEHNKIQNGKAPRDPVTENCVQGEEKESSNDSTSVSAVASNMRDDE ITQDENTVSTSLGHSKDENSKQTCIRIGTKTPKSDSCTPTNTTVEVVGSSGQNGDEKQNI VARKIVKMTKQPAKKKPPPSREKKVTRTILAILLAFIITWAPYNVMVLINTFCAPCIPNT VWTIGYWLCYINSTINPACYALCNATFKKTFKHLLMCHYKNIGATR
Related US Patent	6,288,068
	6,294,554
	6,498,168
	6,500,822
	6,627,644
	6,635,658
	6,645,958
	6,667,301
Target Validation	Click to Find Target Validation Information.
Inhibitor	1'-Benzyl-3-phenyl-[3,4']bipiperidinyl-2,6-dione		[11]
	1,1-diphenyl-2- (3-tropanyl)ethanol		[12]
	1-Methyl-1- (4-pyrrolidin-1-yl-but-2-ynyl)-urea		[13]
	2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]decan-3-one		[14]
	2- (4-Diethylamino-but-2-ynyl)-isoindole-1,3-dione		[15]
	2-Methyl-6-pyrrolidin-1-yl-hex-4-ynal oxime		[16]
	3- (3-benzylamino)-piperidin-2-one		[17]
	3-Methyl-7-pyrrolidin-1-yl-hept-5-yn-2-one		[16]
	3-Tetrazol-2-yl-1-aza-bicyclo[2.2.2]octane		[18]
	4- (4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one		[19]
	6-Dimethylamino-2-methyl-hex-4-ynal oxime		[16]
	7-Dimethylamino-3-methyl-hept-5-yn-2-one		[16]
	7-Dimethylamino-hept-5-yn-2-one		[16]
	7-Dimethylamino-hept-5-yn-2-one oxime		[16]
	7-Pyrrolidin-1-yl-hept-5-yn-2-one		[16]
	7-Pyrrolidin-1-yl-hept-5-yn-2-one oxime		[16]
	A-987306		[20]
	ACECLIDINE		[21]
	Acetic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester		[22]
	BRL-55473		[23]
	Benzoic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester		[24]
	CARAMIPEN		[25]
	FLUMEZAPINE		[26]
	FM1-10		[27]
	FM1-43		[27]
	GNF-PF-5618		[28]
	HIMBACINE		[29]
	ISOCLOZAPINE		[30]
	ISOLOXAPINE		[31]
	METHACHOLINE		[22]
	METHOCTRAMINE		[20]
	METHOCTRAMINE HYDROCHLORIDE		[32]
	N- (4-Dimethylamino-but-2-ynyl)-N-methyl-acetamide		[16]
	N-DESMETHYLCLOZAPINE		[19]
	N-methoxyquinuclidine-3-carboximidoyl chloride		[23]
	N-methoxyquinuclidine-3-carboximidoyl fluoride		[23]
	Propionic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester		[24]
	SCH-211803		[33]
	SULFOARECOLINE		[34]
	Tiotropium Bromide		[35]
	XANOMELINE		[36]
Agonist	CMI-1145		[2]
	CMI-936		[2]
	Oxotremorine		[2]
	PTAC		[4]
Antagonist	(R)-4-[2-[3-		[37][3]
	AF-DX116		[6]
	Gallamine Triethiodide		[7]
	Methylscopolamine		[8]
	Otenzepad		[3]
	Scopolamine		[9][10]
Cross References	3D Structure Related Literature On-Line Medical Dictionary
Ref 1	Psychosis of Alzheimer's disease is associated with elevated muscarinic M2 binding in the cortex. Neurology. 2001 Sep 11;57(5):805-11. To Reference
Ref 2	Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice. Mol Pharmacol. 2002 Nov;62(5):1084-93. To Reference
Ref 3	Beneficial effect of muscarinic-2 antagonist on dilated cardiomyopathy induced by autoimmune mechanism against muscarinic-2 receptor. J Cardiovasc Pharmacol. 2001 Oct;38 Suppl 1:S43-9. To Reference
Ref 4	Function of pulmonary neuronal M(2) muscarinic receptors in stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001 May;163(6):1320-5. To Reference
Ref 5	Generation and pharmacological analysis of M2 and M4 muscarinic receptor knockout mice. Life Sci. 2001 Apr 27;68(22-23):2457-66. To Reference
Ref 6	The 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 7	Cholinergic regulation of the corpora allata in adult male loreyi leafworm Mythimna loreyi. Arch Insect Biochem Physiol. 2002 Apr;49(4):215-24. To Reference
Ref 8	Methylacridinium and its Cholinergic Properties. Neurotox Res. 2009 Jun 30. [Epub ahead of print] To Reference
Ref 9	The amygdala modulates morphine-induced state-dependent memory retrieval via muscarinic acetylcholine receptors. Neuroscience. 2009 May 5;160(2):255-63. Epub 2009 Mar 9. To Reference
Ref 10	Midbrain acetylcholine and glutamate receptors modulate accumbal dopamine release. Neuroreport. 2008 Jun 11;19(9):991-5. To Reference
Ref 11	J 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 12	Bioorg 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 13	J 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 14	J 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 15	Bioorg. Med. Chem. Lett. 7(8):979-984 (1997) To Reference
Ref 16	Bioorg. Med. Chem. Lett. 2(8):803-808 (1992) To Reference
Ref 17	J 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 18	J Med Chem. 1992 Apr 3;35(7):1280-90.Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives. To Reference
Ref 19	J 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 20	J 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 21	J 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 22	J Med Chem. 1998 Jun 4;41(12):2047-55.6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors. To Reference
Ref 23	Bioorg. Med. Chem. Lett. 2(8):791-796 (1992) To Reference
Ref 24	J 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 25	J Med Chem. 1991 Oct;34(10):2984-9.Muscarinic receptor binding profile of para-substituted caramiphen analogues. To Reference
Ref 26	J 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 27	Bioorg 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 28	J 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 29	Bioorg Med Chem Lett. 2004 Aug 2;14(15):3967-70.Himbacine analogs as muscarinic receptor antagonists--effects of tether and heterocyclic variations. To Reference
Ref 30	J 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 31	J 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 32	J Med Chem. 2008 Jul 24;51(14):4150-69. Epub 2008 Jun 28.Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity. To Reference
Ref 33	J Med Chem. 2002 Dec 5;45(25):5415-8.Improving the oral efficacy of CNS drug candidates: discovery of highly orally efficacious piperidinyl piperidine M2 muscarinic receptor antagonists. To Reference
Ref 34	J Med Chem. 1988 Jul;31(7):1312-6.Heterocyclic muscarinic agonists. Synthesis and biological activity of some bicyclic sulfonium arecoline bioisosteres. To Reference
Ref 35	J 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 36	Bioorg. Med. Chem. Lett. 2(8):809-814 (1992) To Reference
Ref 37	Signal 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

Welcome to sign our Guestbook.

If you find any error in data or bug in web service, please kindly report it to Dr. Zhu.

Dr. Chen Yuzong
Deputy Director of Center for Computational Science and Engineering
Professor in Department of Pharmacy
National University of Singapore, Singapore

All rights reserved.