Target Information
| Target General Information | Top | |||||
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| Target ID |
T20709
(Former ID: TTDS00005)
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| Target Name |
Muscarinic acetylcholine receptor M4 (CHRM4)
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| Synonyms |
M4 receptor; CHRM4
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| Gene Name |
CHRM4
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 5 Target-related Diseases | + | ||||
| 1 | Asthma [ICD-11: CA23] | |||||
| 2 | Eye anterior segment structural developmental anomaly [ICD-11: LA11] | |||||
| 3 | Glaucoma [ICD-11: 9C61] | |||||
| 4 | Nausea/vomiting [ICD-11: MD90] | |||||
| 5 | Respiratory system disease [ICD-11: CB40-CB7Z] | |||||
| 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.
Click to Show/Hide
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MANFTPVNGSSGNQSVRLVTSSSHNRYETVEMVFIATVTGSLSLVTVVGNILVMLSIKVN
RQLQTVNNYFLFSLACADLIIGAFSMNLYTVYIIKGYWPLGAVVCDLWLALDYVVSNASV MNLLIISFDRYFCVTKPLTYPARRTTKMAGLMIAAAWVLSFVLWAPAILFWQFVVGKRTV PDNQCFIQFLSNPAVTFGTAIAAFYLPVVIMTVLYIHISLASRSRVHKHRPEGPKEKKAK TLAFLKSPLMKQSVKKPPPGEAAREELRNGKLEEAPPPALPPPPRPVADKDTSNESSSGS ATQNTKERPATELSTTEATTPAMPAPPLQPRALNPASRWSKIQIVTKQTGNECVTAIEIV PATPAGMRPAANVARKFASIARNQVRKKRQMAARERKVTRTIFAILLAFILTWTPYNVMV LVNTFCQSCIPDTVWSIGYWLCYVNSTINPACYALCNATFKKTFRHLLLCQYRNIGTAR Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T95T22 | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 4 Approved Drugs | + | ||||
| 1 | ACECLIDINE | Drug Info | Approved | Glaucoma/ocular hypertension | [2], [3] | |
| 2 | Diphenidol | Drug Info | Approved | Nausea | [3], [4], [5] | |
| 3 | Methacholine Chloride | Drug Info | Approved | bronchial hyperreactivity | [3] | |
| 4 | Tropicamide | Drug Info | Approved | Mydriasis | [6], [7] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Inhibitor | [+] 33 Inhibitor drugs | + | ||||
| 1 | ACECLIDINE | Drug Info | [8] | |||
| 2 | Methacholine Chloride | Drug Info | [10] | |||
| 3 | 1'-Benzyl-3-phenyl-[3,4']bipiperidinyl-2,6-dione | Drug Info | [12] | |||
| 4 | 1-Methyl-1-(4-pyrrolidin-1-yl-but-2-ynyl)-urea | Drug Info | [13] | |||
| 5 | 2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]decan-3-one | Drug Info | [14] | |||
| 6 | 2-Methyl-6-pyrrolidin-1-yl-hex-4-ynal oxime | Drug Info | [15] | |||
| 7 | 3-(3-benzylamino)-piperidin-2-one | Drug Info | [16] | |||
| 8 | 3-Methyl-7-pyrrolidin-1-yl-hept-5-yn-2-one | Drug Info | [15] | |||
| 9 | 3-Tetrazol-2-yl-1-aza-bicyclo[2.2.2]octane | Drug Info | [17] | |||
| 10 | 4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one | Drug Info | [18] | |||
| 11 | 6-Dimethylamino-2-methyl-hex-4-ynal oxime | Drug Info | [15] | |||
| 12 | 7-Dimethylamino-3-methyl-hept-5-yn-2-one | Drug Info | [15] | |||
| 13 | 7-Dimethylamino-hept-5-yn-2-one | Drug Info | [15] | |||
| 14 | 7-Pyrrolidin-1-yl-hept-5-yn-2-one | Drug Info | [15] | |||
| 15 | A-987306 | Drug Info | [19] | |||
| 16 | Acetic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester | Drug Info | [10] | |||
| 17 | Benzoic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester | Drug Info | [22] | |||
| 18 | BRL-55473 | Drug Info | [23] | |||
| 19 | Cremastrine | Drug Info | [25] | |||
| 20 | FLUMEZAPINE | Drug Info | [26] | |||
| 21 | FM1-10 | Drug Info | [27] | |||
| 22 | FM1-43 | Drug Info | [27] | |||
| 23 | GNF-PF-5618 | Drug Info | [28] | |||
| 24 | ISOCLOZAPINE | Drug Info | [29] | |||
| 25 | ISOLOXAPINE | Drug Info | [30] | |||
| 26 | N-(4-Dimethylamino-but-2-ynyl)-N-methyl-acetamide | Drug Info | [15] | |||
| 27 | N-methoxyquinuclidine-3-carboximidoyl chloride | Drug Info | [23] | |||
| 28 | N-methoxyquinuclidine-3-carboximidoyl fluoride | Drug Info | [23] | |||
| 29 | PF-3409409 | Drug Info | [31] | |||
| 30 | Propionic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester | Drug Info | [22] | |||
| 31 | SULFOARECOLINE | Drug Info | [33] | |||
| 32 | VU10007 | Drug Info | [34] | |||
| 33 | VU10010 | Drug Info | [34] | |||
| Antagonist | [+] 2 Antagonist drugs | + | ||||
| 1 | Diphenidol | Drug Info | [9] | |||
| 2 | Tropicamide | Drug Info | [1], [11] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | AF-DX-384 | Drug Info | [20], [21] | |||
| Agonist | [+] 3 Agonist drugs | + | ||||
| 1 | CMI-1145 | Drug Info | [24] | |||
| 2 | CMI-936 | Drug Info | [24] | |||
| 3 | PTAC | Drug Info | [32] | |||
| 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 Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| 2 | Cholinergic synapse | |||||
| 3 | Regulation of actin cytoskeleton | |||||
| Panther Pathway | [+] 4 Panther Pathways | + | ||||
| 1 | Alzheimer disease-amyloid secretase pathway | |||||
| 2 | Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway | |||||
| 3 | Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway | |||||
| 4 | Muscarinic acetylcholine receptor 2 and 4 signaling pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Muscarinic acetylcholine receptors | |||||
| 2 | G alpha (i) signalling events | |||||
| WikiPathways | [+] 6 WikiPathways | + | ||||
| 1 | Monoamine GPCRs | |||||
| 2 | Calcium Regulation in the Cardiac Cell | |||||
| 3 | Regulation of Actin Cytoskeleton | |||||
| 4 | GPCRs, Class A Rhodopsin-like | |||||
| 5 | GPCR ligand binding | |||||
| 6 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | The muscarinic receptor antagonist tropicamide suppresses tremulous jaw movements in a rodent model of parkinsonian tremor: possible role of M4 rec... Psychopharmacology (Berl). 2007 Oct;194(3):347-59. | |||||
| 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 | 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: 7163). | |||||
| REF 5 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 016033. | |||||
| REF 6 | 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: 7319). | |||||
| REF 7 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 040064. | |||||
| REF 8 | 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 9 | Diphenidol-related diamines as novel muscarinic M4 receptor antagonists. Bioorg Med Chem Lett. 2008 May 1;18(9):2972-6. | |||||
| REF 10 | 6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors. J Med Chem. 1998 Jun 4;41(12):2047-55. | |||||
| REF 11 | 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 12 | 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 13 | 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 14 | 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 15 | Cholinergic agents: aldehyde, ketone, and oxime analogues of the muscarinic agonist UH5, Bioorg. Med. Chem. Lett. 2(8):803-808 (1992). | |||||
| REF 16 | 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 17 | Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives. J Med Chem. 1992 Apr 3;35(7):1280-90. | |||||
| REF 18 | 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 19 | 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 20 | 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 21 | 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 22 | 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 23 | 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 24 | Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice. Mol Pharmacol. 2002 Nov;62(5):1084-93. | |||||
| REF 25 | Cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata. J Nat Prod. 2005 Apr;68(4):572-3. | |||||
| REF 26 | 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 27 | Design and synthesis of a fluorescent muscarinic antagonist. Bioorg Med Chem Lett. 2008 Jan 15;18(2):825-7. | |||||
| REF 28 | 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 29 | 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 30 | 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 31 | Design, synthesis and evaluation of N-[(3S)-pyrrolidin-3-yl]benzamides as selective noradrenaline reuptake inhibitors: CNS penetration in a more po... Bioorg Med Chem Lett. 2009 Aug 15;19(16):4579-83. | |||||
| REF 32 | 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 33 | Heterocyclic muscarinic agonists. Synthesis and biological activity of some bicyclic sulfonium arecoline bioisosteres. J Med Chem. 1988 Jul;31(7):1312-6. | |||||
| REF 34 | An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission. Nat Chem Biol. 2008 Jan;4(1):42-50. | |||||
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