Target Information
Target General Infomation | |||||
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Target ID |
T20709
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Former ID |
TTDS00005
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Target Name |
Muscarinic acetylcholine receptor M4
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Gene Name |
CHRM4
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Synonyms |
M4 receptor; CHRM4
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Target Type |
Successful
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Disease | Asthma [ICD10: J45] | ||||
Attention deficit hyperactivity disorder [ICD9: 314; ICD10: F90] | |||||
Glaucoma [ICD9: 365; ICD10: H40-H42] | |||||
Mydriasis diagnosis [ICD9: 379.43; ICD10: H57.0] | |||||
Nausea; Vomiting; Emesis [ICD9:787, 787.0; ICD10: R11] | |||||
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 inhibition of adenylate cyclase.
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BioChemical Class |
GPCR rhodopsin
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Target Validation |
T20709
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UniProt ID | |||||
Sequence |
MANFTPVNGSSGNQSVRLVTSSSHNRYETVEMVFIATVTGSLSLVTVVGNILVMLSIKVN
RQLQTVNNYFLFSLACADLIIGAFSMNLYTVYIIKGYWPLGAVVCDLWLALDYVVSNASV MNLLIISFDRYFCVTKPLTYPARRTTKMAGLMIAAAWVLSFVLWAPAILFWQFVVGKRTV PDNQCFIQFLSNPAVTFGTAIAAFYLPVVIMTVLYIHISLASRSRVHKHRPEGPKEKKAK TLAFLKSPLMKQSVKKPPPGEAAREELRNGKLEEAPPPALPPPPRPVADKDTSNESSSGS ATQNTKERPATELSTTEATTPAMPAPPLQPRALNPASRWSKIQIVTKQTGNECVTAIEIV PATPAGMRPAANVARKFASIARNQVRKKRQMAARERKVTRTIFAILLAFILTWTPYNVMV LVNTFCQSCIPDTVWSIGYWLCYVNSTINPACYALCNATFKKTFRHLLLCQYRNIGTAR |
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Drugs and Mode of Action | |||||
Drug(s) | ACECLIDINE | Drug Info | Approved | Glaucoma | [539906], [551871] |
Diphenidol | Drug Info | Approved | Nausea; Vomiting; Emesis | [538470], [542172], [551871] | |
METHACHOLINE | Drug Info | Approved | Asthma | [526519], [530155], [533484], [542461], [551871] | |
Tropicamide | Drug Info | Approved | Mydriasis diagnosis | [538161], [542342] | |
Inhibitor | 1'-Benzyl-3-phenyl-[3,4']bipiperidinyl-2,6-dione | Drug Info | [533345] | ||
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-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] | |||
CREMASTRINE | Drug Info | [527523] | |||
FLUMEZAPINE | Drug Info | [533165] | |||
FM1-10 | Drug Info | [529178] | |||
FM1-43 | Drug Info | [529178] | |||
GNF-PF-5618 | Drug Info | [527653] | |||
ISOCLOZAPINE | Drug Info | [530313] | |||
ISOLOXAPINE | Drug Info | [533577] | |||
METHACHOLINE | Drug Info | [534645] | |||
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] | |||
PF-3409409 | Drug Info | [530265] | |||
Propionic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester | Drug Info | [525826] | |||
SULFOARECOLINE | Drug Info | [533450] | |||
VU10007 | Drug Info | [529197] | |||
VU10010 | Drug Info | [529197] | |||
Modulator | AF-DX-384 | Drug Info | |||
Agonist | CMI-1145 | Drug Info | [535589] | ||
CMI-936 | Drug Info | [535589] | |||
PTAC | Drug Info | [535182] | |||
Antagonist | Diphenidol | Drug Info | [536678] | ||
Tropicamide | Drug Info | [535597], [536441] | |||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
KEGG Pathway | Neuroactive ligand-receptor interaction | ||||
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 | |||||
Reactome | Muscarinic acetylcholine receptors | ||||
G alpha (i) signalling events | |||||
WikiPathways | Monoamine GPCRs | ||||
Calcium Regulation in the Cardiac Cell | |||||
Regulation of Actin Cytoskeleton | |||||
GPCRs, Class A Rhodopsin-like | |||||
GPCR ligand binding | |||||
GPCR downstream signaling | |||||
References | |||||
Ref 526519 | Muscarinic M3-receptors mediate cholinergic synergism of mitogenesis in airway smooth muscle. Am J Respir Cell Mol Biol. 2003 Feb;28(2):257-62. | ||||
Ref 530155 | Muscarinic 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 533484 | Dissociation 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 538161 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 040064. | ||||
Ref 538470 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 016033. | ||||
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 542172 | (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: 7163). | ||||
Ref 542342 | (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: 7319). | ||||
Ref 525826 | 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. | ||||
Ref 527029 | 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. | ||||
Ref 527344 | J Med Chem. 1992 Apr 3;35(7):1280-90.Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives. | ||||
Ref 527523 | J Nat Prod. 2005 Apr;68(4):572-3.Cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata. | ||||
Ref 527653 | 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. | ||||
Ref 528735 | 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. | ||||
Ref 529178 | Bioorg Med Chem Lett. 2008 Jan 15;18(2):825-7. Epub 2007 Nov 17.Design and synthesis of a fluorescent muscarinic antagonist. | ||||
Ref 529197 | Nat Chem Biol. 2008 Jan;4(1):42-50. Epub 2007 Dec 2.An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission. | ||||
Ref 529789 | J 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 530265 | 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. | ||||
Ref 530313 | J Med Chem. 1990 Feb;33(2):809-14.Chloro-substituted, sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents. | ||||
Ref 531079 | 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. | ||||
Ref 533165 | 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. | ||||
Ref 533345 | 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. | ||||
Ref 533450 | J Med Chem. 1988 Jul;31(7):1312-6.Heterocyclic muscarinic agonists. Synthesis and biological activity of some bicyclic sulfonium arecoline bioisosteres. | ||||
Ref 533577 | 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. | ||||
Ref 534044 | 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. | ||||
Ref 534645 | J Med Chem. 1998 Jun 4;41(12):2047-55.6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors. | ||||
Ref 534723 | 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. | ||||
Ref 535182 | 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 535589 | Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice. Mol Pharmacol. 2002 Nov;62(5):1084-93. | ||||
Ref 535597 | Zebrafish M2 muscarinic acetylcholine receptor: cloning, pharmacological characterization, expression patterns and roles in embryonic bradycardia. Br J Pharmacol. 2002 Nov;137(6):782-92. | ||||
Ref 536441 | The muscarinic receptor antagonist tropicamide suppresses tremulous jaw movements in a rodent model of parkinsonian tremor: possible role of M4 receptors. Psychopharmacology (Berl). 2007 Oct;194(3):347-59. Epub 2007 Jun 27. | ||||
Ref 536678 | Diphenidol-related diamines as novel muscarinic M4 receptor antagonists. Bioorg Med Chem Lett. 2008 May 1;18(9):2972-6. Epub 2008 Mar 23. |
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