TTD Target ID: TTDS00006

Target Information
Name	Muscarinic acetylcholine receptor M5
Type of target	Successful target
Synonyms	M5 receptor
Disease	Opioid dependence    [1]
	Schizophrenia    [2]
Drug(s)	Atropine		Approved	Organophosphate poisoning	[3][4][5][6]
	Homatropine Methylbromide		Approved	Peptic ulcer disease	[7]
	Metixene		Approved	Parkinson's disease	[7]
	Promazine		Approved	Psychomotor agitation	[8]
BioChemical Class	G-protein coupled receptor (rhodopsin family)
Pathway	Calcium signaling pathway
	Neuroactive ligand-receptor interaction
	Regulation of actin cytoskeleton
UniProt ID	P08912
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	MEGDSYHNATTVNGTPVNHQPLERHRLWEVITIAAVTAVVSLITIVGNVLVMISFKVNSQ LKTVNNYYLLSLACADLIIGIFSMNLYTTYILMGRWALGSLACDLWLALDYVASNASVMN LLVISFDRYFSITRPLTYRAKRTPKRAGIMIGLAWLISFILWAPAILCWQYLVGKRTVPL DECQIQFLSEPTITFGTAIAAFYIPVSVMTILYCRIYRETEKRTKDLADLQGSDSVTKAE KRKPAHRALFRSCLRCPRPTLAQRERNQASWSSSRRSTSTTGKPSQATGPSANWAKAEQL TTCSSYPSSEDEDKPATDPVLQVVYKSQGKESPGEEFSAEETEETFVKAETEKSDYDTPN YLLSPAAAHRPKSQKCVAYKFRLVVKADGNQETNNGCHKVKIMPCPFPVAKEPSTKGLNP NPSHQMTKRKRVVLVKERKAAQTLSAILLAFIITWTPYNIMVLVSTFCDKCVPVTLWHLG YWLCYVNSTVNPICYALCNRTFRKTFKMLLLCRWKKKKVEEKLYWQGNSKLP
Target Validation	Click to Find Target Validation Information.
Inhibitor	1'-Benzyl-3-phenyl-[3,4']bipiperidinyl-2,6-dione		[9]
	1-Methyl-1- (4-pyrrolidin-1-yl-but-2-ynyl)-urea		[10]
	2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]decan-3-one		[11]
	2-Methyl-6-pyrrolidin-1-yl-hex-4-ynal oxime		[12]
	3- (3-benzylamino)-piperidin-2-one		[13]
	3-Methyl-7-pyrrolidin-1-yl-hept-5-yn-2-one		[12]
	3-Tetrazol-2-yl-1-aza-bicyclo[2.2.2]octane		[14]
	4- (4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one		[15]
	6-Dimethylamino-2-methyl-hex-4-ynal oxime		[12]
	7-Dimethylamino-3-methyl-hept-5-yn-2-one		[12]
	7-Dimethylamino-hept-5-yn-2-one		[12]
	7-Dimethylamino-hept-5-yn-2-one oxime		[12]
	7-Pyrrolidin-1-yl-hept-5-yn-2-one		[12]
	7-Pyrrolidin-1-yl-hept-5-yn-2-one oxime		[12]
	ACECLIDINE		[16]
	Acetic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester		[17]
	BRL-55473		[18]
	Benzoic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester		[17]
	CREMASTRINE		[19]
	FLUMEZAPINE		[20]
	FM1-10		[21]
	FM1-43		[21]
	GNF-PF-5618		[22]
	ISOCLOZAPINE		[23]
	ISOLOXAPINE		[24]
	N- (4-Dimethylamino-but-2-ynyl)-N-methyl-acetamide		[12]
	N-DESMETHYLCLOZAPINE		[15]
	N-methoxyquinuclidine-3-carboximidoyl chloride		[18]
	N-methoxyquinuclidine-3-carboximidoyl fluoride		[18]
	PF-3409409		[25]
	SULFOARECOLINE		[26]
	VU0119498		[27]
	VU0238429		[27]
	XANOMELINE		[28]
Antagonist	Atropine		[3][4][5][6]
	Homatropine Methylbromide		[7]
	Metixene		[7]
Binder	Promazine		[8]
Cross References	3D Structure Related Literature On-Line Medical Dictionary
Ref 1	Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia. Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11452-7. Epub 2002 Aug 1. To Reference
Ref 2	Systematic review of antipsychotics for the treatment of hospital-associated delirium in medically or surgically ill patients. Ann Pharmacother. 2006 Nov;40(11):1966-73. Epub 2006 Oct 17. To Reference
Ref 3	Additive Protective Effects of Donepezil and Nicotine Against Salsolinol-Induced Cytotoxicity in SH-SY5Y Cells. Neurotox Res. 2009 Mar 20. [Epub ahead of print] To Reference
Ref 4	Loss of M2 muscarinic receptor function inhibits development of hypoxic bradycardia and alters cardiac beta-adrenergic sensitivity in larval zebrafish (Danio rerio). Am J Physiol Regul Integr Comp Physiol. 2009 Aug;297(2):R412-20. Epub 2009 Jun 10. To Reference
Ref 5	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 6	The muscarinic antagonists aprophen and benactyzine are noncompetitive inhibitors of the nicotinic acetylcholine receptor. Mol Pharmacol. 1987 Nov;32(5):678-85. To Reference
Ref 7	Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. To Reference
Ref 8	Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. Life Sci. 1988;43(5):405-12. To Reference
Ref 9	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 10	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 11	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 12	Bioorg. Med. Chem. Lett. 2(8):803-808 (1992) To Reference
Ref 13	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 14	J Med Chem. 1992 Apr 3;35(7):1280-90.Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives. To Reference
Ref 15	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 16	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 17	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 18	Bioorg. Med. Chem. Lett. 2(8):791-796 (1992) To Reference
Ref 19	J Nat Prod. 2005 Apr;68(4):572-3.Cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata. To Reference
Ref 20	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 21	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 22	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 23	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 24	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 25	Bioorg Med Chem Lett. 2009 Aug 15;19(16):4579-83. Epub 2009 Jul 2.Design, synthesis and evaluation of N-[(3S)-pyrrolidin-3-yl]benzamides as selective noradrenaline reuptake inhibitors: CNS penetration in a more polar template. To Reference
Ref 26	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 27	J Med Chem. 2009 Jun 11;52(11):3445-8.Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins. To Reference
Ref 28	Bioorg. Med. Chem. Lett. 2(8):809-814 (1992) To Reference

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