Target Information

Target General Information

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Target ID

T46185 (Former ID: TTDS00003)

Target Name

Muscarinic acetylcholine receptor M2 (CHRM2)

Synonyms

M2 receptor; CHRM2

Gene Name

CHRM2

Target Type

Successful target

[1]

Disease

[+] 6 Target-related Diseases

Asthma [ICD-11: CA23]

Glaucoma [ICD-11: 9C61]

Muscle disorder [ICD-11: FB32-FB3Z]

Peptic ulcer [ICD-11: DA61]

Respiratory system disease [ICD-11: CB40-CB7Z]

Sebaceous gland disorder [ICD-11: ED91]

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.

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BioChemical Class

GPCR rhodopsin

UniProt ID

ACM2_HUMAN

Sequence

MNNSTNSSNNSLALTSPYKTFEVVFIVLVAGSLSLVTIIGNILVMVSIKVNRHLQTVNNY
FLFSLACADLIIGVFSMNLYTLYTVIGYWPLGPVVCDLWLALDYVVSNASVMNLLIISFD
RYFCVTKPLTYPVKRTTKMAGMMIAAAWVLSFILWAPAILFWQFIVGVRTVEDGECYIQF
FSNAAVTFGTAIAAFYLPVIIMTVLYWHISRASKSRIKKDKKEPVANQDPVSPSLVQGRI
VKPNNNNMPSSDDGLEHNKIQNGKAPRDPVTENCVQGEEKESSNDSTSVSAVASNMRDDE
ITQDENTVSTSLGHSKDENSKQTCIRIGTKTPKSDSCTPTNTTVEVVGSSGQNGDEKQNI
VARKIVKMTKQPAKKKPPPSREKKVTRTILAILLAFIITWAPYNVMVLINTFCAPCIPNT
VWTIGYWLCYINSTINPACYALCNATFKKTFKHLLMCHYKNIGATR

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3D Structure

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PDB

ADReCS ID

BADD_A00659 ; BADD_A01381

Drugs and Modes of Action

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Approved Drug(s)

[+] 5 Approved Drugs

ACECLIDINE

Drug Info

Approved

Glaucoma/ocular hypertension

[2], [3]

Gallamine Triethiodide

Drug Info

Approved

Stabilize muscle contraction

[4]

Methacholine Chloride

Drug Info

Approved

bronchial hyperreactivity

[3]

Methylscopolamine

Drug Info

Approved

Peptic ulcer

[3], [5], [6]

SMT-D002

Drug Info

Approved

Seborrhea

[7]

Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

FP-1097

Drug Info

Phase 2

Urinary incontinence

[8]

Discontinued Drug(s)

[+] 8 Discontinued Drugs

Otenzepad

Drug Info

Discontinued in Phase 2

Heart failure

[9], [10]

PSD-506

Drug Info

Discontinued in Phase 2

Overactive bladder

[11]

SCH-211803

Drug Info

Discontinued in Phase 1

Parkinson disease

[12]

Alvameline

Drug Info

Terminated

Alzheimer disease

[13]

AQ-RA-741

Drug Info

Terminated

Cardiovascular disease

[14], [15]

BIBN-140

Drug Info

Terminated

Alzheimer disease

[16]

BIBN-99

Drug Info

Terminated

Alzheimer disease

[17]

Sch-57790

Drug Info

Terminated

Alzheimer disease

[18], [19]

Mode of Action

[+] 4 Modes of Action

Inhibitor

[+] 35 Inhibitor drugs

ACECLIDINE

Drug Info

[20]

Methacholine Chloride

Drug Info

[22]

SCH-211803

Drug Info

[28]

HIMBACINE

Drug Info

[31]

1'-Benzyl-3-phenyl-[3,4']bipiperidinyl-2,6-dione

Drug Info

[34]

1,1-diphenyl-2-(3-tropanyl)ethanol

Drug Info

[35]

1-Methyl-1-(4-pyrrolidin-1-yl-but-2-ynyl)-urea

Drug Info

[36]

2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]decan-3-one

Drug Info

[37]

2-(4-Diethylamino-but-2-ynyl)-isoindole-1,3-dione

Drug Info

[38]

2-Methyl-6-pyrrolidin-1-yl-hex-4-ynal oxime

Drug Info

[39]

3-(3-benzylamino)-piperidin-2-one

Drug Info

[40]

3-Methyl-7-pyrrolidin-1-yl-hept-5-yn-2-one

Drug Info

[39]

3-Tetrazol-2-yl-1-aza-bicyclo[2.2.2]octane

Drug Info

[41]

4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one

Drug Info

[42]

6-Dimethylamino-2-methyl-hex-4-ynal oxime

Drug Info

[39]

7-Dimethylamino-3-methyl-hept-5-yn-2-one

Drug Info

[39]

7-Dimethylamino-hept-5-yn-2-one

Drug Info

[39]

7-Pyrrolidin-1-yl-hept-5-yn-2-one

Drug Info

[39]

A-987306

Drug Info

[43]

Acetic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester

Drug Info

[22]

Benzoic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester

Drug Info

[46]

BRL-55473

Drug Info

[47]

CARAMIPEN

Drug Info

[48]

FLUMEZAPINE

Drug Info

[50]

FM1-10

Drug Info

[51]

FM1-43

Drug Info

[51]

GNF-PF-5618

Drug Info

[52]

ISOCLOZAPINE

Drug Info

[53]

ISOLOXAPINE

Drug Info

[54]

METHOCTRAMINE

Drug Info

[43]

N-(4-Dimethylamino-but-2-ynyl)-N-methyl-acetamide

Drug Info

[39]

N-methoxyquinuclidine-3-carboximidoyl chloride

Drug Info

[47]

N-methoxyquinuclidine-3-carboximidoyl fluoride

Drug Info

[47]

Propionic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester

Drug Info

[46]

SULFOARECOLINE

Drug Info

[56]

Antagonist

[+] 6 Antagonist drugs

Gallamine Triethiodide

Drug Info

[21]

Methylscopolamine

Drug Info

[23]

FP-1097

Drug Info

[25]

Otenzepad

Drug Info

[26]

Sch-57790

Drug Info

[32]

(R)-4-[2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl]piperidine-1-carboxylic acid amide (Ro-320-6206)

Drug Info

[26], [33]

Agonist

[+] 5 Agonist drugs

SMT-D002

Drug Info

[24]

CMI-1145

Drug Info

[49]

CMI-936

Drug Info

[49]

Green tea

Drug Info

[49]

PTAC

Drug Info

[55]

Modulator

[+] 6 Modulator drugs

PSD-506

Drug Info

[27]

Alvameline

Drug Info

[13]

AQ-RA-741

Drug Info

[29]

BIBN-140

Drug Info

[16]

BIBN-99

Drug Info

[30]

AF-DX-384

Drug Info

[44], [45]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 6 KEGG Pathways

Calcium signaling pathway

cAMP signaling pathway

Neuroactive ligand-receptor interaction

PI3K-Akt signaling pathway

Cholinergic synapse

Regulation of actin cytoskeleton

Panther Pathway

[+] 4 Panther Pathways

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

[+] 1 Pathwhiz Pathways

Muscle/Heart Contraction

Reactome

[+] 2 Reactome Pathways

Muscarinic acetylcholine receptors

G alpha (i) signalling events

WikiPathways

[+] 8 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

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

The amygdala modulates morphine-induced state-dependent memory retrieval via muscarinic acetylcholine receptors. Neuroscience. 2009 May 5;160(2):255-63.

REF 2

URL: 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 3

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 4

Drug information of Gallamine Triethiodide, 2008. eduDrugs.

REF 5

REF 6

Drug information of Methylscopolamine, 2008. eduDrugs.

REF 7

Clinical pipeline report, company report or official report of Summit.

REF 8

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019662)

REF 9

REF 10

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001216)

REF 11

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022973)

REF 12

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015639)

REF 13

In 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 14

REF 15

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002261)

REF 16

Therapeutic potential of CNS-active M2 antagonists: novel structures and pharmacology. Life Sci. 1993;52(5-6):497-503.

REF 17

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002066)

REF 18

REF 19

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011087)

REF 20

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. J Med Chem. 1993 Apr 2;36(7):842-7.

REF 21

Cholinergic regulation of the corpora allata in adult male loreyi leafworm Mythimna loreyi. Arch Insect Biochem Physiol. 2002 Apr;49(4):215-24.

REF 22

6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors. J Med Chem. 1998 Jun 4;41(12):2047-55.

REF 23

Methylacridinium and its cholinergic properties. Neurotox Res. 2009 Nov;16(4):372-7.

REF 24

Demonstration of bladder selective muscarinic receptor binding by intravesical oxybutynin to treat overactive bladder. J Urol. 2004 Nov;172(5 Pt 1):2059-64.

REF 25

Clinical pipeline report, company report or official report of FemmePharma.

REF 26

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.

REF 27

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

REF 28

Improving the oral efficacy of CNS drug candidates: discovery of highly orally efficacious piperidinyl piperidine M2 muscarinic receptor antagonists. J Med Chem. 2002 Dec 5;45(25):5415-8.

REF 29

Pharmacological profile of selective muscarinic receptor antagonists on guinea-pig ileal smooth muscle. Eur J Pharmacol. 1994 Mar 3;253(3):275-81.

REF 30

Characterization of BIBN 99: a lipophilic and selective muscarinic M2 receptor antagonist. Eur J Pharmacol. 1993 Sep 21;242(1):23-30.

REF 31

Himbacine analogs as muscarinic receptor antagonists--effects of tether and heterocyclic variations. Bioorg Med Chem Lett. 2004 Aug 2;14(15):3967-70.

REF 32

SCH 57790: a novel M2 receptor selective antagonist. Life Sci. 1999;64(6-7):535-9.

REF 33

Signal transduction underlying carbachol-induced contraction of human urinary bladder. J Pharmacol Exp Ther. 2004 Jun;309(3):1148-53.

REF 34

Synthesis and biological evaluation of [125I]- and [123I]-4-iododexetimide, a potent muscarinic cholinergic receptor antagonist. J Med Chem. 1989 May;32(5):1057-62.

REF 35

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 acetylch... Bioorg Med Chem Lett. 2009 Aug 15;19(16):4560-2.

REF 36

Urea and 2-imidazolidone derivatives of the muscarinic agents oxotremorine and N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide. J Med Chem. 1992 Aug 21;35(17):3270-9.

REF 37

Synthesis and modeling studies of a potent conformationally rigid muscarinic agonist: 1-azabicyclo[2.2.1]heptanespirofuranone. J Med Chem. 1998 Oct 22;41(22):4181-5.

REF 38

Design of dual acting anticonvulsant-antimuscarinic succinimide and hydantoin derivatives, Bioorg. Med. Chem. Lett. 7(8):979-984 (1997).

REF 39

Cholinergic agents: aldehyde, ketone, and oxime analogues of the muscarinic agonist UH5, Bioorg. Med. Chem. Lett. 2(8):803-808 (1992).

REF 40

Designing active template molecules by combining computational de novo design and human chemist's expertise. J Med Chem. 2007 Apr 19;50(8):1925-32.

REF 41

Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives. J Med Chem. 1992 Apr 3;35(7):1280-90.

REF 42

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 rec... J Med Chem. 2010 Sep 9;53(17):6386-97.

REF 43

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... J Med Chem. 2008 Nov 27;51(22):7094-8.

REF 44

M2/M4 muscarinic receptor binding in the anterior cingulate cortex in schizophrenia and mood disorders. Brain Res Bull. 2005 May 15;65(5):397-403.

REF 45

M2 receptor binding of the selective antagonist AF-DX 384: possible involvement of the common allosteric site. Mol Pharmacol. 1998 Feb;53(2):304-12.

REF 46

6beta-Acyloxy(nor)tropanes: affinities for antagonist/agonist binding sites on transfected and native muscarinic receptors. J Med Chem. 2000 Jun 29;43(13):2514-22.

REF 47

A 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 48

Muscarinic receptor binding profile of para-substituted caramiphen analogues. J Med Chem. 1991 Oct;34(10):2984-9.

REF 49

Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice. Mol Pharmacol. 2002 Nov;62(5):1084-93.

REF 50

Synthesis and pharmacological evaluation of a series of 4-piperazinylpyrazolo[3,4-b]- and -[4,3-b][1,5]benzodiazepines as potential anxiolytics. J Med Chem. 1989 Dec;32(12):2573-82.

REF 51

Design and synthesis of a fluorescent muscarinic antagonist. Bioorg Med Chem Lett. 2008 Jan 15;18(2):825-7.

REF 52

Nocardimicins A, B, C, D, E, and F, siderophores with muscarinic M3 receptor inhibiting activity from Nocardia sp. TP-A0674. J Nat Prod. 2005 Jul;68(7):1061-5.

REF 53

Chloro-substituted, sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents. J Med Chem. 1990 Feb;33(2):809-14.

REF 54

Synthesis of clozapine analogues and their affinity for clozapine and spiroperidol binding sites in rat brain. J Med Chem. 1981 Sep;24(9):1021-6.

REF 55

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.

REF 56

Heterocyclic muscarinic agonists. Synthesis and biological activity of some bicyclic sulfonium arecoline bioisosteres. J Med Chem. 1988 Jul;31(7):1312-6.

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