Therapeutic Targets Database
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TTD Target ID: TTDS00002

Target Information
NameMuscarinic acetylcholine receptor M1    
Type of targetSuccessful target    
SynonymsM1 receptor    
DiseaseAlzheimer's disease
[ICD9: 331.0   ICD10: G30]
[1]
Bronchospasm (histamine induced)
[ICD9: 728.85   ICD10: R25.2]
[2]
Cognitive deficits
[ICD9: 290-294, 294.0, 780.09, 780.9, 780.93   ICD10: F01-F07, F04, R41.3]
[3]
Schizophrenia
[ICD9: 295   ICD10: F20]
[4]
Drug(s)BenztropineApprovedParkinson's disease[5][6]
BiperidenApprovedParkinson's disease[7]
ClidiniumApprovedAbdominal/stomach pain[8]
CycrimineApprovedParkinson's disease[9]
DicyclomineApprovedIrritable bowel syndrome[10][11]
EthopropazineApprovedParkinson's disease[12]
GlycopyrrolateApprovedAnesthetic[13][14]
OxyphenoniumApprovedSpasm[15]
PirenzepineApprovedPeptic ulcer disease[16][2]
PropanthelineApprovedExcessive sweating (hyperhidrosis)[17]
TrihexyphenidylApprovedParkinson's disease[18]
Darotropium + 642444Phase IIICOPD[19]
GSK961081Phase II completedChronic Obstructive Pulmonary Disease (COPD)[19]
Sabcomeline hydrochloridePhase IIaCardiovascular diseases[20]
GSK573719Phase IIChronic Obstructive Pulmonary Disease (COPD)[19]
Xanomeline tartratePhase IIAlzheimer's disease[20][21]
GSK1034702Phase I completedSchizophrenia, Dementia[19]
DarotropiumSuspended in Phase II in GSK 2009 ReportCOPD[19]
RevatropateDiscontinued in Phase IChronic obstructive pulmonary disease[22]
Talsaclidine fumarateDiscontinuedAlzheimer's disease[20][1]
Talsaclidine isomerDiscontinuedAlzheimer's disease[20][1]
BioChemical ClassG-protein coupled receptor (rhodopsin family)    
PathwayCalcium signaling pathway
Neuroactive ligand-receptor interaction
Regulation of actin cytoskeleton
UniProt IDP11229
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.    
SequenceMNTSAPPAVSPNITVLAPGKGPWQVAFIGITTGLLSLATVTGNLLVLISFKVNTELKTVN NYFLLSLACADLIIGTFSMNLYTTYLLMGHWALGTLACDLWLALDYVASNASVMNLLLIS FDRYFSVTRPLSYRAKRTPRRAALMIGLAWLVSFVLWAPAILFWQYLVGERTVLAGQCYI QFLSQPIITFGTAMAAFYLPVTVMCTLYWRIYRETENRARELAALQGSETPGKGGGSSSS SERSQPGAEGSPETPPGRCCRCCRAPRLLQAYSWKEEEEEDEGSMESLTSSEGEEPGSEV VIKMPMVDPEAQAPTKQPPRSSPNTVKRPTKKGRDRAGKGQKPRGKEQLAKRKTFSLVKE KKAARTLSAILLAFILTWTPYNIMVLVSTFCKDCVPETLWELGYWLCYVNSTINPMCYAL CNKAFRDTFRLLLLCRWDKRRWRKIPKRPGSVHRTPSRQC
Related US Patent6,288,068
6,294,554
6,627,645
Target ValidationClick to Find Target Validation Information.    
Inhibitor1'-Benzyl-3-phenyl-[3,4']bipiperidinyl-2,6-dione[23]
1,1-diphenyl-2- (3-tropanyl)ethanol[24]
1-Methyl-1- (4-pyrrolidin-1-yl-but-2-ynyl)-urea[25]
2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]decan-3-one[26]
2- (4-Diethylamino-but-2-ynyl)-isoindole-1,3-dione[27]
2-Methyl-6-pyrrolidin-1-yl-hex-4-ynal oxime[28]
3- (3-benzylamino)-piperidin-2-one[29]
3-Methyl-7-pyrrolidin-1-yl-hept-5-yn-2-one[28]
3-Tetrazol-2-yl-1-aza-bicyclo[2.2.2]octane[30]
3alpha- (bis-chloro-phenylmethoxy)tropane[31]
4- (4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one[32]
6-Dimethylamino-2-methyl-hex-4-ynal oxime[28]
7-Dimethylamino-3-methyl-hept-5-yn-2-one[28]
7-Dimethylamino-hept-5-yn-2-one[28]
7-Dimethylamino-hept-5-yn-2-one oxime[28]
7-Pyrrolidin-1-yl-hept-5-yn-2-one[28]
7-Pyrrolidin-1-yl-hept-5-yn-2-one oxime[28]
A-987306[33]
ACECLIDINE[34]
AMINOBENZTROPINE[35]
Acetic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester[36]
Arecoline[37]
BI-1356[38]
BRL-55473[39]
Benzoic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester[40]
Bo (15)PZ[41]
CARAMIPEN[42]
CREMASTRINE[43]
DIFLUOROBENZTROPINE[31]
FLUMEZAPINE[44]
FM1-10[45]
FM1-43[45]
GNF-PF-5618[46]
HIMBACINE[47]
ISOCLOZAPINE[48]
ISOLOXAPINE[49]
N- (4-Dimethylamino-but-2-ynyl)-N-methyl-acetamide[28]
N-methoxyquinuclidine-3-carboximidoyl chloride[39]
N-methoxyquinuclidine-3-carboximidoyl fluoride[39]
Propionic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester[40]
R-dimethindene[50]
RR (17)PZ[41]
SB-202026[51]
SULFOARECOLINE[52]
Tiotropium Bromide[53]
XANOMELINE[54]
Agonist77-LH-28-1[20]
AC-260584[20]
AC-42[20]
AF150 (S)[55][56]
AF267B[55][56]
Darotropium[19]
Darotropium + 642444[19]
GSK1034702[19]
GSK573719[19]
GSK961081[19]
LY-593039[20]
NGX-267[20]
Sabcomeline[20]
Sabcomeline hydrochloride[20]
Talsaclidine fumarate[20][1]
Talsaclidine isomer[20][1]
WAY-132983[20][1]
Xanomeline tartrate[20][21]
AntagonistBenztropine[5][6]
Biperiden[7]
Clidinium[8]
Dicyclomine[10][11]
Ethopropazine[12]
Glycopyrrolate[13][14]
Oxyphenonium[15]
Pirenzepine[16][2]
Propantheline[17]
Revatropate[22]
Trihexyphenidyl[18]
BinderCycrimine[9]
MultitargetGSK961081[19]
Revatropate[22]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Memory-related task performance by aged rhesus monkeys administered the muscarinic M(1)-preferring agonist, talsaclidine. Psychopharmacology (Berl). 2002 Jul;162(3):292-300. Epub 2002 May 29. To Reference
Ref 2The effect of muscarinic receptor blockers on non-specific bronchial reactivity in patients with bronchial asthma. Pneumonol Alergol Pol. 1992;60(11-12):32-6. To Reference
Ref 3Trends Pharmacol Sci. 2001 Aug;22(8):409-14.Therapeutic opportunities from muscarinic receptor research. To Reference
Ref 4Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice. Eur J Pharmacol. 2009 Jan 28;603(1-3):147-9. Epub 2008 Dec 16. To Reference
Ref 5Formulation and biopharmaceutical evaluation of transdermal patch containing benztropine. Int J Pharm. 2008 Jun 5;357(1-2):55-60. Epub 2008 Jan 20. To Reference
Ref 6Muscarinic preferential M(1) receptor antagonists enhance the discriminative-stimulus effects of cocaine in rats. Pharmacol Biochem Behav. 2007 Oct;87(4):400-4. Epub 2007 Jun 2. To Reference
Ref 7Evaluation of in vivo binding properties of 3H-NMPB and 3H-QNB in mouse brain. J Neural Transm. 1999;106(7-8):583-92. To Reference
Ref 8Accidental acute clidinium toxicity. Emerg Med J. 2009 Jun;26(6):460. To Reference
Ref 9Capillary gas chromatography of trihexyphenidyl, procyclidine and cycrimine in biological fluids. J Chromatogr. 1989 Sep 29;494:135-42. To Reference
Ref 10Characterization of undifferentiated muscarinic thyroid cells in Fisher rats.. Endocrinol Nutr. 2009 Mar;56(3):106-11. Epub 2009 May 18. To Reference
Ref 11Fustin flavonoid attenuates beta-amyloid (1-42)-induced learning impairment. J Neurosci Res. 2009 Jun 16. [Epub ahead of print] To Reference
Ref 12The relative selectivity of anticholinergic drugs for the M1 and M2 muscarinic receptor subtypes. Mov Disord. 1986;1(2):135-44. To Reference
Ref 13Autonomic cardiovascular control during a novel pharmacologic alternative to ganglionic blockade. Clin Pharmacol Ther. 2008 May;83(5):692-701. Epub 2007 Aug 8. To Reference
Ref 14A pharmacological profile of glycopyrrolate: interactions at the muscarinic acetylcholine receptor. Gen Pharmacol. 1992 Nov;23(6):1165-70. To Reference
Ref 15Ultraviolet spectroscopic estimation of microenvironments and bitter tastes of oxyphenonium bromide in cyclodextrin solutions. J Pharm Sci. 1999 Aug;88(8):759-62. To Reference
Ref 16Negative crosstalk between M1 and M2 muscarinic autoreceptors involves endogenous adenosine activating A1 receptors at the rat motor endplate. Neurosci Lett. 2009 Aug 14;459(3):127-31. Epub 2009 May 7. To Reference
Ref 17Involvement of the peripheral cholinergic muscarinic system in the compensatory ovarian hypertrophy in the rat. Exp Biol Med (Maywood). 2004 Sep;229(8):793-805. To Reference
Ref 18The role of M1 muscarinic cholinergic receptors in the discriminative stimulus properties of N-desmethylclozapine and the atypical antipsychotic drug clozapine in rats. Psychopharmacology (Berl). 2009 Apr;203(2):295-301. Epub 2008 Aug 7. To Reference
Ref 19GSK. Product Development Pipeline. February 2009. To Reference
Ref 20Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists. Eur J Pharmacol. 2009 Mar 1;605(1-3):53-6. Epub 2009 Jan 11. To Reference
Ref 21On the unique binding and activating properties of xanomeline at the M1 muscarinic acetylcholine receptor. Mol Pharmacol. 1998 Jun;53(6):1120-30. To Reference
Ref 22Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91. To Reference
Ref 23J 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 24Bioorg 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 25J 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 26J 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 27Bioorg. Med. Chem. Lett. 7(8):979-984 (1997) To Reference
Ref 28Bioorg. Med. Chem. Lett. 2(8):803-808 (1992) To Reference
Ref 29J 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 30J Med Chem. 1992 Apr 3;35(7):1280-90.Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives. To Reference
Ref 31J Med Chem. 2006 Oct 19;49(21):6391-9.Structure-activity relationship studies on a novel series of (S)-2beta-substituted 3alpha-[bis(4-fluoro- or 4-chlorophenyl)methoxy]tropane analogues for in vivo investigation. To Reference
Ref 32J 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 33J 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 34J 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 35J Med Chem. 1997 Mar 14;40(6):851-7.3'-Chloro-3 alpha-(diphenylmethoxy)tropane but not 4'-chloro-3 alpha-(diphenylmethoxy)tropane produces a cocaine-like behavioral profile. To Reference
Ref 36J Med Chem. 1998 Jun 4;41(12):2047-55.6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors. To Reference
Ref 37Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. To Reference
Ref 38J Med Chem. 2007 Dec 27;50(26):6450-3. Epub 2007 Dec 1.8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. To Reference
Ref 39Bioorg. Med. Chem. Lett. 2(8):791-796 (1992) To Reference
Ref 40J 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 41J Med Chem. 2005 Dec 1;48(24):7847-59.On the use of nonfluorescent dye labeled ligands in FRET-based receptor binding studies. To Reference
Ref 42J Med Chem. 1991 Oct;34(10):2984-9.Muscarinic receptor binding profile of para-substituted caramiphen analogues. To Reference
Ref 43J Nat Prod. 2005 Apr;68(4):572-3.Cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata. To Reference
Ref 44J 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 45Bioorg 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 46J 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 47Bioorg 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 48J 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 49J 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 50J Med Chem. 2009 Sep 10;52(17):5307-10.Characterization of novel selective H1-antihistamines for clinical evaluation in the treatment of insomnia. To Reference
Ref 51J Med Chem. 1997 Dec 19;40(26):4265-80.Design of [R-(Z)]-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitri le (SB 202026), a functionally selective azabicyclic muscarinic M1 agonist incorporating the N-methoxy imidoyl nitrile group as a novel ester bioisostere. To Reference
Ref 52J Med Chem. 1988 Jul;31(7):1312-6.Heterocyclic muscarinic agonists. Synthesis and biological activity of some bicyclic sulfonium arecoline bioisosteres. To Reference
Ref 53J 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 54J Med Chem. 1992 Oct 30;35(22):4011-9.Novel functional M1 selective muscarinic agonists. 2. Synthesis and structure-activity relationships of 3-pyrazinyl-1,2,5,6-tetrahydro-1-methylpyridines. Construction of a molecular model for the M1 pharmacophore. To Reference
Ref 55M1 muscarinic agonists target major hallmarks of Alzheimer's disease--an update. Curr Alzheimer Res. 2007 Dec;4(5):577-80. To Reference
Ref 56M1 muscarinic agonists can modulate some of the hallmarks in Alzheimer's disease: implications in future therapy. J Mol Neurosci. 2003;20(3):349-56. To Reference



 

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National University of Singapore, Singapore


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