Target Information

Target General Infomation
Target ID
T20709
Former ID
TTDS00005
Target Name
Muscarinic acetylcholine receptor M4
Gene Name
CHRM4
Synonyms
M4 receptor; CHRM4
Target Type
Successful
Disease Attention deficit hyperactivity disorder [ICD9: 314; ICD10: F90]
Asthma [ICD10: J45]
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.
BioChemical Class
GPCR rhodopsin
Target Validation
T20709
UniProt ID
P08173
Sequence
MANFTPVNGSSGNQSVRLVTSSSHNRYETVEMVFIATVTGSLSLVTVVGNILVMLSIKVN
RQLQTVNNYFLFSLACADLIIGAFSMNLYTVYIIKGYWPLGAVVCDLWLALDYVVSNASV
MNLLIISFDRYFCVTKPLTYPARRTTKMAGLMIAAAWVLSFVLWAPAILFWQFVVGKRTV
PDNQCFIQFLSNPAVTFGTAIAAFYLPVVIMTVLYIHISLASRSRVHKHRPEGPKEKKAK
TLAFLKSPLMKQSVKKPPPGEAAREELRNGKLEEAPPPALPPPPRPVADKDTSNESSSGS
ATQNTKERPATELSTTEATTPAMPAPPLQPRALNPASRWSKIQIVTKQTGNECVTAIEIV
PATPAGMRPAANVARKFASIARNQVRKKRQMAARERKVTRTIFAILLAFILTWTPYNVMV
LVNTFCQSCIPDTVWSIGYWLCYVNSTINPACYALCNATFKKTFRHLLLCQYRNIGTAR
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 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 538161FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 040064.
Ref 538470FDA 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 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 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
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 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 527344J Med Chem. 1992 Apr 3;35(7):1280-90.Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives.
Ref 527523J Nat Prod. 2005 Apr;68(4):572-3.Cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata.
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 529197Nat Chem Biol. 2008 Jan;4(1):42-50. Epub 2007 Dec 2.An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.
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 530265Bioorg 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 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 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 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 535589Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice. Mol Pharmacol. 2002 Nov;62(5):1084-93.
Ref 535597Zebrafish M2 muscarinic acetylcholine receptor: cloning, pharmacological characterization, expression patterns and roles in embryonic bradycardia. Br J Pharmacol. 2002 Nov;137(6):782-92.
Ref 536441The 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 536678Diphenidol-related diamines as novel muscarinic M4 receptor antagonists. Bioorg Med Chem Lett. 2008 May 1;18(9):2972-6. Epub 2008 Mar 23.
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).

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