Target Information
Target General Information | Top | |||||
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Target ID |
T46185
(Former ID: TTDS00003)
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Target Name |
Muscarinic acetylcholine receptor M2 (CHRM2)
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Synonyms |
M2 receptor; CHRM2
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Gene Name |
CHRM2
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 6 Target-related Diseases | + | ||||
1 | Asthma [ICD-11: CA23] | |||||
2 | Glaucoma [ICD-11: 9C61] | |||||
3 | Muscle disorder [ICD-11: FB32-FB3Z] | |||||
4 | Peptic ulcer [ICD-11: DA61] | |||||
5 | Respiratory system disease [ICD-11: CB40-CB7Z] | |||||
6 | 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
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UniProt ID | ||||||
Sequence |
MNNSTNSSNNSLALTSPYKTFEVVFIVLVAGSLSLVTIIGNILVMVSIKVNRHLQTVNNY
FLFSLACADLIIGVFSMNLYTLYTVIGYWPLGPVVCDLWLALDYVVSNASVMNLLIISFD RYFCVTKPLTYPVKRTTKMAGMMIAAAWVLSFILWAPAILFWQFIVGVRTVEDGECYIQF FSNAAVTFGTAIAAFYLPVIIMTVLYWHISRASKSRIKKDKKEPVANQDPVSPSLVQGRI VKPNNNNMPSSDDGLEHNKIQNGKAPRDPVTENCVQGEEKESSNDSTSVSAVASNMRDDE ITQDENTVSTSLGHSKDENSKQTCIRIGTKTPKSDSCTPTNTTVEVVGSSGQNGDEKQNI VARKIVKMTKQPAKKKPPPSREKKVTRTILAILLAFIITWAPYNVMVLINTFCAPCIPNT VWTIGYWLCYINSTINPACYALCNATFKKTFKHLLMCHYKNIGATR Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
ADReCS ID | BADD_A00659 ; BADD_A01381 |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 5 Approved Drugs | + | ||||
1 | ACECLIDINE | Drug Info | Approved | Glaucoma/ocular hypertension | [2], [3] | |
2 | Gallamine Triethiodide | Drug Info | Approved | Stabilize muscle contraction | [4] | |
3 | Methacholine Chloride | Drug Info | Approved | bronchial hyperreactivity | [3] | |
4 | Methylscopolamine | Drug Info | Approved | Peptic ulcer | [3], [5], [6] | |
5 | SMT-D002 | Drug Info | Approved | Seborrhea | [7] | |
Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
1 | FP-1097 | Drug Info | Phase 2 | Urinary incontinence | [8] | |
Discontinued Drug(s) | [+] 8 Discontinued Drugs | + | ||||
1 | Otenzepad | Drug Info | Discontinued in Phase 2 | Heart failure | [9], [10] | |
2 | PSD-506 | Drug Info | Discontinued in Phase 2 | Overactive bladder | [11] | |
3 | SCH-211803 | Drug Info | Discontinued in Phase 1 | Parkinson disease | [12] | |
4 | Alvameline | Drug Info | Terminated | Alzheimer disease | [13] | |
5 | AQ-RA-741 | Drug Info | Terminated | Cardiovascular disease | [14], [15] | |
6 | BIBN-140 | Drug Info | Terminated | Alzheimer disease | [16] | |
7 | BIBN-99 | Drug Info | Terminated | Alzheimer disease | [17] | |
8 | Sch-57790 | Drug Info | Terminated | Alzheimer disease | [18], [19] | |
Mode of Action | [+] 4 Modes of Action | + | ||||
Inhibitor | [+] 35 Inhibitor drugs | + | ||||
1 | ACECLIDINE | Drug Info | [20] | |||
2 | Methacholine Chloride | Drug Info | [22] | |||
3 | SCH-211803 | Drug Info | [28] | |||
4 | HIMBACINE | Drug Info | [31] | |||
5 | 1'-Benzyl-3-phenyl-[3,4']bipiperidinyl-2,6-dione | Drug Info | [34] | |||
6 | 1,1-diphenyl-2-(3-tropanyl)ethanol | Drug Info | [35] | |||
7 | 1-Methyl-1-(4-pyrrolidin-1-yl-but-2-ynyl)-urea | Drug Info | [36] | |||
8 | 2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]decan-3-one | Drug Info | [37] | |||
9 | 2-(4-Diethylamino-but-2-ynyl)-isoindole-1,3-dione | Drug Info | [38] | |||
10 | 2-Methyl-6-pyrrolidin-1-yl-hex-4-ynal oxime | Drug Info | [39] | |||
11 | 3-(3-benzylamino)-piperidin-2-one | Drug Info | [40] | |||
12 | 3-Methyl-7-pyrrolidin-1-yl-hept-5-yn-2-one | Drug Info | [39] | |||
13 | 3-Tetrazol-2-yl-1-aza-bicyclo[2.2.2]octane | Drug Info | [41] | |||
14 | 4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one | Drug Info | [42] | |||
15 | 6-Dimethylamino-2-methyl-hex-4-ynal oxime | Drug Info | [39] | |||
16 | 7-Dimethylamino-3-methyl-hept-5-yn-2-one | Drug Info | [39] | |||
17 | 7-Dimethylamino-hept-5-yn-2-one | Drug Info | [39] | |||
18 | 7-Pyrrolidin-1-yl-hept-5-yn-2-one | Drug Info | [39] | |||
19 | A-987306 | Drug Info | [43] | |||
20 | Acetic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester | Drug Info | [22] | |||
21 | Benzoic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester | Drug Info | [46] | |||
22 | BRL-55473 | Drug Info | [47] | |||
23 | CARAMIPEN | Drug Info | [48] | |||
24 | FLUMEZAPINE | Drug Info | [50] | |||
25 | FM1-10 | Drug Info | [51] | |||
26 | FM1-43 | Drug Info | [51] | |||
27 | GNF-PF-5618 | Drug Info | [52] | |||
28 | ISOCLOZAPINE | Drug Info | [53] | |||
29 | ISOLOXAPINE | Drug Info | [54] | |||
30 | METHOCTRAMINE | Drug Info | [43] | |||
31 | N-(4-Dimethylamino-but-2-ynyl)-N-methyl-acetamide | Drug Info | [39] | |||
32 | N-methoxyquinuclidine-3-carboximidoyl chloride | Drug Info | [47] | |||
33 | N-methoxyquinuclidine-3-carboximidoyl fluoride | Drug Info | [47] | |||
34 | Propionic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester | Drug Info | [46] | |||
35 | SULFOARECOLINE | Drug Info | [56] | |||
Antagonist | [+] 6 Antagonist drugs | + | ||||
1 | Gallamine Triethiodide | Drug Info | [21] | |||
2 | Methylscopolamine | Drug Info | [23] | |||
3 | FP-1097 | Drug Info | [25] | |||
4 | Otenzepad | Drug Info | [26] | |||
5 | Sch-57790 | Drug Info | [32] | |||
6 | (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 | + | ||||
1 | SMT-D002 | Drug Info | [24] | |||
2 | CMI-1145 | Drug Info | [49] | |||
3 | CMI-936 | Drug Info | [49] | |||
4 | Green tea | Drug Info | [49] | |||
5 | PTAC | Drug Info | [55] | |||
Modulator | [+] 6 Modulator drugs | + | ||||
1 | PSD-506 | Drug Info | [27] | |||
2 | Alvameline | Drug Info | [13] | |||
3 | AQ-RA-741 | Drug Info | [29] | |||
4 | BIBN-140 | Drug Info | [16] | |||
5 | BIBN-99 | Drug Info | [30] | |||
6 | AF-DX-384 | Drug Info | [44], [45] |
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"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 | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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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 | 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: 316). | |||||
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 | 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: 309). | |||||
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 | 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: 8584). | |||||
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 | 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: 350). | |||||
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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