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 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.
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 [1], [2]
Diphenidol Drug Info Approved Nausea; Vomiting; Emesis [3], [4], [2]
METHACHOLINE Drug Info Approved Asthma [5], [6], [7], [8], [2]
Tropicamide Drug Info Approved Mydriasis diagnosis [9], [10]
Inhibitor 1'-Benzyl-3-phenyl-[3,4']bipiperidinyl-2,6-dione Drug Info [11]
1-Methyl-1-(4-pyrrolidin-1-yl-but-2-ynyl)-urea Drug Info [12]
2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]decan-3-one Drug Info [13]
2-Methyl-6-pyrrolidin-1-yl-hex-4-ynal oxime Drug Info [14]
3-(3-benzylamino)-piperidin-2-one Drug Info [15]
3-Methyl-7-pyrrolidin-1-yl-hept-5-yn-2-one Drug Info [14]
3-Tetrazol-2-yl-1-aza-bicyclo[2.2.2]octane Drug Info [16]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info [17]
6-Dimethylamino-2-methyl-hex-4-ynal oxime Drug Info [14]
7-Dimethylamino-3-methyl-hept-5-yn-2-one Drug Info [14]
7-Dimethylamino-hept-5-yn-2-one Drug Info [14]
7-Pyrrolidin-1-yl-hept-5-yn-2-one Drug Info [14]
A-987306 Drug Info [18]
ACECLIDINE Drug Info [19]
Acetic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester Drug Info [20]
Benzoic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester Drug Info [21]
BRL-55473 Drug Info [22]
CREMASTRINE Drug Info [23]
FLUMEZAPINE Drug Info [24]
FM1-10 Drug Info [25]
FM1-43 Drug Info [25]
GNF-PF-5618 Drug Info [26]
ISOCLOZAPINE Drug Info [27]
ISOLOXAPINE Drug Info [28]
METHACHOLINE Drug Info [20]
N-(4-Dimethylamino-but-2-ynyl)-N-methyl-acetamide Drug Info [14]
N-methoxyquinuclidine-3-carboximidoyl chloride Drug Info [22]
N-methoxyquinuclidine-3-carboximidoyl fluoride Drug Info [22]
PF-3409409 Drug Info [29]
Propionic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester Drug Info [21]
SULFOARECOLINE Drug Info [30]
VU10007 Drug Info [31]
VU10010 Drug Info [31]
Modulator AF-DX-384 Drug Info
Agonist CMI-1145 Drug Info [32]
CMI-936 Drug Info [32]
PTAC Drug Info [33]
Antagonist Diphenidol Drug Info [34]
Tropicamide Drug Info [35], [36]
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 1(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 2Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 3FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 016033.
REF 4(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 5Muscarinic M3-receptors mediate cholinergic synergism of mitogenesis in airway smooth muscle. Am J Respir Cell Mol Biol. 2003 Feb;28(2):257-62.
REF 6Muscarinic 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 7Dissociation 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 8(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 9FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 040064.
REF 10(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 11J 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 12J 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 13J 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 14Cholinergic agents: aldehyde, ketone, and oxime analogues of the muscarinic agonist UH5, Bioorg. Med. Chem. Lett. 2(8):803-808 (1992).
REF 15J 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 16J Med Chem. 1992 Apr 3;35(7):1280-90.Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives.
REF 17J 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 18J 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 19J 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 20J Med Chem. 1998 Jun 4;41(12):2047-55.6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors.
REF 21J 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 22A 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 23J Nat Prod. 2005 Apr;68(4):572-3.Cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata.
REF 24J 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 25Bioorg Med Chem Lett. 2008 Jan 15;18(2):825-7. Epub 2007 Nov 17.Design and synthesis of a fluorescent muscarinic antagonist.
REF 26J 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 27J Med Chem. 1990 Feb;33(2):809-14.Chloro-substituted, sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents.
REF 28J 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 29Bioorg 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 30J Med Chem. 1988 Jul;31(7):1312-6.Heterocyclic muscarinic agonists. Synthesis and biological activity of some bicyclic sulfonium arecoline bioisosteres.
REF 31Nat Chem Biol. 2008 Jan;4(1):42-50. Epub 2007 Dec 2.An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.
REF 32Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice. Mol Pharmacol. 2002 Nov;62(5):1084-93.
REF 33Function 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 34Diphenidol-related diamines as novel muscarinic M4 receptor antagonists. Bioorg Med Chem Lett. 2008 May 1;18(9):2972-6. Epub 2008 Mar 23.
REF 35Zebrafish M2 muscarinic acetylcholine receptor: cloning, pharmacological characterization, expression patterns and roles in embryonic bradycardia. Br J Pharmacol. 2002 Nov;137(6):782-92.
REF 36The 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.

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