Target Information

Target General Infomation
Target ID
T46185
Former ID
TTDS00003
Target Name
Muscarinic acetylcholine receptor M2
Gene Name
CHRM2
Synonyms
M2 receptor; CHRM2
Target Type
Successful
Disease Alzheimer disease [ICD9: 331; ICD10: G30]
Asthma [ICD10: J45]
Cardiovascular disorder [ICD10: I00-I99]
Glaucoma [ICD9: 365; ICD10: H40-H42]
Heart failure [ICD9: 428; ICD10: I50]
Nausea; Addiction [ICD9: 303-305, 787.0; ICD10: F10-F19, R11]
Overactive bladder disorder [ICD9: 188, 596.51; ICD10: C67, N32.81]
Peptic ulcer [ICD9: 531-534; ICD10: K25-K27]
Parkinson's disease [ICD9: 332; ICD10: G20]
Stabilize muscle contractions [ICD10: M00-M99]
Seborrhea [ICD10: L21]
Urinary incontinence [ICD9: 788.3; ICD10: N39.3, N39.4, R32]
Unspecified [ICD code not available]
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. Primary transducing effect is adenylate cyclase inhibition. Signaling promotes phospholipase C activity, leading to the release of inositol trisphosphate (IP3); this then triggers calcium ion release into the cytosol.
BioChemical Class
GPCR rhodopsin
Target Validation
T46185
UniProt ID
P08172
Sequence
MTLHNNSTTSPLFPNISSSWIHSPSDAGLPPGTVTHFGSYNVSRAAGNFSSPDGTTDDPL
GGHTVWQVVFIAFLTGILALVTIIGNILVIVSFKVNKQLKTVNNYFLLSLACADLIIGVI
SMNLFTTYIIMNRWALGNLACDLWLAIDYVASNASVMNLLVISFDRYFSITRPLTYRAKR
TTKRAGVMIGLAWVISFVLWAPAILFWQYFVGKRTVPPGECFIQFLSEPTITFGTAIAAF
YMPVTIMTILYWRIYKETEKRTKELAGLQASGTEAETENFVHPTGSSRSCSSYELQQQSM
KRSNRRKYGRCHFWFTTKSWKPSSEQMDQDHSSSDSWNNNDAAASLENSASSDEEDIGSE
TRAIYSIVLKLPGHSTILNSTKLPSSDNLQVPEEELGMVDLERKADKLQAQKSVDDGGSF
PKSFSKLPIQLESAVDTAKTSDVNSSVGKSTATLPLSFKEATLAKRFALKTRSQITKRKR
MSLVKEKKAAQTLSAILLAFIITWTPYNIMVLVNTFCDSCIPKTFWNLGYWLCYINSTVN
PVCYALCNKTFRTTFKMLLLCQCDKKKRRKQQYQQRQSVIFHKRAPEQAL
Structure
1LUB; 3UON; 4MQS; 4MQT
Drugs and Mode of Action
Drug(s) ACECLIDINE Drug Info Approved Glaucoma [539906], [551871]
Gallamine Triethiodide Drug Info Approved Stabilize muscle contractions [550753]
METHACHOLINE Drug Info Approved Asthma [526519], [530155], [533484], [542461], [551871]
Methylscopolamine Drug Info Approved Peptic ulcer [540146], [550719], [551871]
Scopolamine Drug Info Approved Nausea; Addiction [540261], [551436]
SMT-D002 Drug Info Approved Seborrhea [551707]
FP-1097 Drug Info Phase 2 Urinary incontinence [547822]
Otenzepad Drug Info Discontinued in Phase 2 Heart failure [540091], [544816]
PSD-506 Drug Info Discontinued in Phase 2 Overactive bladder disorder [548196]
SCH-211803 Drug Info Discontinued in Phase 1 Parkinson's disease [547376]
Alvameline Drug Info Terminated Alzheimer disease [534674]
AQ-RA-741 Drug Info Terminated Cardiovascular disorder [543206], [545137]
BIBN-140 Drug Info Terminated Alzheimer disease [534038]
BIBN-99 Drug Info Terminated Alzheimer disease [545083]
HIMBACINE Drug Info Terminated Discovery agent [540212], [546219]
Sch-57790 Drug Info Terminated Alzheimer disease [540439], [546916]
Antagonist (R)-4-[2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl]piperidine-1-carboxylic acid amide (Ro-320-6206) Drug Info [535357], [535903]
FP-1097 Drug Info [549828]
Gallamine Triethiodide Drug Info [535420]
Methylscopolamine Drug Info [537554]
Otenzepad Drug Info [535357]
Sch-57790 Drug Info [525433]
Scopolamine Drug Info [536730], [537137]
Inhibitor 1'-Benzyl-3-phenyl-[3,4']bipiperidinyl-2,6-dione Drug Info [533345]
1,1-diphenyl-2-(3-tropanyl)ethanol Drug Info [530266]
1-Methyl-1-(4-pyrrolidin-1-yl-but-2-ynyl)-urea Drug Info [527029]
2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]decan-3-one Drug Info [534723]
2-(4-Diethylamino-but-2-ynyl)-isoindole-1,3-dione Drug Info [551341]
2-Methyl-6-pyrrolidin-1-yl-hex-4-ynal oxime Drug Info [551235]
3-(3-benzylamino)-piperidin-2-one Drug Info [528735]
3-Methyl-7-pyrrolidin-1-yl-hept-5-yn-2-one Drug Info [551235]
3-Tetrazol-2-yl-1-aza-bicyclo[2.2.2]octane Drug Info [527344]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info [531079]
6-Dimethylamino-2-methyl-hex-4-ynal oxime Drug Info [551235]
7-Dimethylamino-3-methyl-hept-5-yn-2-one Drug Info [551235]
7-Dimethylamino-hept-5-yn-2-one Drug Info [551235]
7-Pyrrolidin-1-yl-hept-5-yn-2-one Drug Info [551235]
A-987306 Drug Info [529789]
ACECLIDINE Drug Info [534044]
Acetic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester Drug Info [534645]
Benzoic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester Drug Info [525826]
BRL-55473 Drug Info [551234]
CARAMIPEN Drug Info [529957]
FLUMEZAPINE Drug Info [533165]
FM1-10 Drug Info [529178]
FM1-43 Drug Info [529178]
GNF-PF-5618 Drug Info [527653]
HIMBACINE Drug Info [527126]
ISOCLOZAPINE Drug Info [530313]
ISOLOXAPINE Drug Info [533577]
METHACHOLINE Drug Info [534645]
METHOCTRAMINE Drug Info [529789]
N-(4-Dimethylamino-but-2-ynyl)-N-methyl-acetamide Drug Info [551235]
N-methoxyquinuclidine-3-carboximidoyl chloride Drug Info [551234]
N-methoxyquinuclidine-3-carboximidoyl fluoride Drug Info [551234]
Propionic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester Drug Info [525826]
SCH-211803 Drug Info [526473]
SULFOARECOLINE Drug Info [533450]
Modulator AF-DX-384 Drug Info
Alvameline Drug Info [534674]
AQ-RA-741 Drug Info [533924]
BIBN-140 Drug Info [534038]
BIBN-99 Drug Info [533931]
PSD-506 Drug Info [1572591]
Agonist CMI-1145 Drug Info [535589]
CMI-936 Drug Info [535589]
Oxotremorine Drug Info [535589]
PTAC Drug Info [535182]
SMT-D002 Drug Info [527286]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Calcium signaling pathway
cAMP signaling pathway
Neuroactive ligand-receptor interaction
PI3K-Akt signaling pathway
Cholinergic synapse
Regulation of actin cytoskeleton
PANTHER Pathway Alzheimer disease-amyloid secretase pathway
Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway
Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway
Muscarinic acetylcholine receptor 2 and 4 signaling pathway
PathWhiz Pathway Muscle/Heart Contraction
Reactome Muscarinic acetylcholine receptors
G alpha (i) signalling events
WikiPathways SIDS Susceptibility Pathways
Monoamine GPCRs
Calcium Regulation in the Cardiac Cell
Regulation of Actin Cytoskeleton
GPCRs, Class A Rhodopsin-like
GPCR ligand binding
GPCR downstream signaling
GPCRs, Other
References
Ref 526519Muscarinic M3-receptors mediate cholinergic synergism of mitogenesis in airway smooth muscle. Am J Respir Cell Mol Biol. 2003 Feb;28(2):257-62.
Ref 530155Muscarinic M3 receptor stimulation increases cigarette smoke-induced IL-8 secretion by human airway smooth muscle cells. Eur Respir J. 2009 Dec;34(6):1436-43.
Ref 533484Dissociation constants and relative efficacies of acetylcholine, (+)- and (-)-methacholine at muscarinic receptors in the guinea-pig ileum. Br J Pharmacol. 1986 Sep;89(1):7-13.
Ref 534038Therapeutic potential of CNS-active M2 antagonists: novel structures and pharmacology. Life Sci. 1993;52(5-6):497-503.
Ref 534674In vivo muscarinic cholinergic mediated effects of Lu 25-109, a M1 agonist and M2/M3 antagonist in vitro. Psychopharmacology (Berl). 1998 Jun;137(3):233-40.
Ref 539906(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 288).
Ref 540091(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 309).
Ref 540146(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 316).
Ref 540212(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 324).
Ref 540261(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 330).
Ref 540439(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 350).
Ref 542461(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7438).
Ref 543206(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8584).
Ref 544816Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001216)
Ref 545083Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002066)
Ref 545137Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002261)
Ref 546219Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006949)
Ref 546916Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011087)
Ref 547376Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015639)
Ref 547822Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019662)
Ref 548196Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022973)
Ref 550719Drug information of Methylscopolamine, 2008. eduDrugs.
Ref 550753Drug information of Gallamine Triethiodide, 2008. eduDrugs.
Ref 551436Drug Information of Calcidiol from nextbio research in illumina. 2015.
Ref 551707Clinical pipeline report, company report or official report of Summit.
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref
Ref 525433SCH 57790: a novel M2 receptor selective antagonist. Life Sci. 1999;64(6-7):535-9.
Ref 525826J 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.
Ref 526473J 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.
Ref 527029J 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.
Ref 527126Bioorg Med Chem Lett. 2004 Aug 2;14(15):3967-70.Himbacine analogs as muscarinic receptor antagonists--effects of tether and heterocyclic variations.
Ref 527286Demonstration of bladder selective muscarinic receptor binding by intravesical oxybutynin to treat overactive bladder. J Urol. 2004 Nov;172(5 Pt 1):2059-64.
Ref 527344J Med Chem. 1992 Apr 3;35(7):1280-90.Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives.
Ref 527653J 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.
Ref 528735J 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.
Ref 529178Bioorg Med Chem Lett. 2008 Jan 15;18(2):825-7. Epub 2007 Nov 17.Design and synthesis of a fluorescent muscarinic antagonist.
Ref 529789J 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.
Ref 529957J Med Chem. 1991 Oct;34(10):2984-9.Muscarinic receptor binding profile of para-substituted caramiphen analogues.
Ref 530266Bioorg 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.
Ref 530313J Med Chem. 1990 Feb;33(2):809-14.Chloro-substituted, sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents.
Ref 531079J 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.
Ref 533165J 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.
Ref 533345J Med Chem. 1989 May;32(5):1057-62.Synthesis and biological evaluation of [125I]- and [123I]-4-iododexetimide, a potent muscarinic cholinergic receptor antagonist.
Ref 533450J Med Chem. 1988 Jul;31(7):1312-6.Heterocyclic muscarinic agonists. Synthesis and biological activity of some bicyclic sulfonium arecoline bioisosteres.
Ref 533577J Med Chem. 1981 Sep;24(9):1021-6.Synthesis of clozapine analogues and their affinity for clozapine and spiroperidol binding sites in rat brain.
Ref 533924Pharmacological profile of selective muscarinic receptor antagonists on guinea-pig ileal smooth muscle. Eur J Pharmacol. 1994 Mar 3;253(3):275-81.
Ref 533931Characterization of BIBN 99: a lipophilic and selective muscarinic M2 receptor antagonist. Eur J Pharmacol. 1993 Sep 21;242(1):23-30.
Ref 534038Therapeutic potential of CNS-active M2 antagonists: novel structures and pharmacology. Life Sci. 1993;52(5-6):497-503.
Ref 534044J 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.
Ref 534645J Med Chem. 1998 Jun 4;41(12):2047-55.6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors.
Ref 534674In vivo muscarinic cholinergic mediated effects of Lu 25-109, a M1 agonist and M2/M3 antagonist in vitro. Psychopharmacology (Berl). 1998 Jun;137(3):233-40.
Ref 534723J 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.
Ref 535182Function 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.
Ref 535357Beneficial 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.
Ref 535420Cholinergic regulation of the corpora allata in adult male loreyi leafworm Mythimna loreyi. Arch Insect Biochem Physiol. 2002 Apr;49(4):215-24.
Ref 535589Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice. Mol Pharmacol. 2002 Nov;62(5):1084-93.
Ref 535903Signal transduction underlying carbachol-induced contraction of human urinary bladder. J Pharmacol Exp Ther. 2004 Jun;309(3):1148-53. Epub 2004 Feb 9.
Ref 536730Midbrain acetylcholine and glutamate receptors modulate accumbal dopamine release. Neuroreport. 2008 Jun 11;19(9):991-5.
Ref 537137The amygdala modulates morphine-induced state-dependent memory retrieval via muscarinic acetylcholine receptors. Neuroscience. 2009 May 5;160(2):255-63. Epub 2009 Mar 9.
Ref 537554Methylacridinium and its Cholinergic Properties. Neurotox Res. 2009 Jun 30.
Ref 549828Clinical pipeline report, company report or official report of FemmePharma.
Ref 551234A novel and selective class of azabicyclic muscarinic agonists incorporating an N-methoxy imidoyl halide or nitrile functionality, Bioorg. Med. Chem. Lett. 2(8):791-796 (1992).
Ref 551235Cholinergic agents: aldehyde, ketone, and oxime analogues of the muscarinic agonist UH5, Bioorg. Med. Chem. Lett. 2(8):803-808 (1992).
Ref 551341Design of dual acting anticonvulsant-antimuscarinic succinimide and hydantoin derivatives, Bioorg. Med. Chem. Lett. 7(8):979-984 (1997).
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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