Therapeutic Targets Database
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TTD Target ID: TTDS00005

Target Information
NameMuscarinic acetylcholine receptor M4    
Type of targetSuccessful target    
SynonymsM4 receptor    
DiseaseAnalgesics    [1]
Manic disorder    [2]
Neurologic and psychiatric diseases    [3]
Pain, unspecified    [1]
Parkinsonian symptoms    [4]
Drug(s)DiphenidolApprovedNausea and vomiting[5]
TropicamideApprovedDiagnostic aids for mydriasis[6][7]
BioChemical ClassG-protein coupled receptor (rhodopsin family)    
PathwayNeuroactive ligand-receptor interaction
Regulation of actin cytoskeleton
UniProt IDP08173
FunctionThe 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.    
SequenceMANFTPVNGSSGNQSVRLVTSSSHNRYETVEMVFIATVTGSLSLVTVVGNILVMLSIKVN RQLQTVNNYFLFSLACADLIIGAFSMNLYTVYIIKGYWPLGAVVCDLWLALDYVVSNASV MNLLIISFDRYFCVTKPLTYPARRTTKMAGLMIAAAWVLSFVLWAPAILFWQFVVGKRTV PDNQCFIQFLSNPAVTFGTAIAAFYLPVVIMTVLYIHISLASRSRVHKHRPEGPKEKKAK TLAFLKSPLMKQSVKKPPPGEAAREELRNGKLEEAPPPALPPPPRPVADKDTSNESSSGS ATQNTKERPATELSTTEATTPAMPAPPLQPRALNPASRWSKIQIVTKQTGNECVTAIEIV PATPAGMRPAANVARKFASIARNQVRKKRQMAARERKVTRTIFAILLAFILTWTPYNVMV LVNTFCQSCIPDTVWSIGYWLCYVNSTINPACYALCNATFKKTFRHLLLCQYRNIGTAR
Related US Patent6,251,916
6,500,837
6,559,171
6,627,645
Target ValidationClick to Find Target Validation Information.    
Inhibitor1'-Benzyl-3-phenyl-[3,4']bipiperidinyl-2,6-dione[8]
1-Methyl-1- (4-pyrrolidin-1-yl-but-2-ynyl)-urea[9]
2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]decan-3-one[10]
2-Methyl-6-pyrrolidin-1-yl-hex-4-ynal oxime[11]
3- (3-benzylamino)-piperidin-2-one[12]
3-Methyl-7-pyrrolidin-1-yl-hept-5-yn-2-one[11]
3-Tetrazol-2-yl-1-aza-bicyclo[2.2.2]octane[13]
4- (4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one[14]
6-Dimethylamino-2-methyl-hex-4-ynal oxime[11]
7-Dimethylamino-3-methyl-hept-5-yn-2-one[11]
7-Dimethylamino-hept-5-yn-2-one[11]
7-Dimethylamino-hept-5-yn-2-one oxime[11]
7-Pyrrolidin-1-yl-hept-5-yn-2-one[11]
7-Pyrrolidin-1-yl-hept-5-yn-2-one oxime[11]
A-987306[15]
ACECLIDINE[16]
Acetic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester[17]
BRL-55473[18]
Benzoic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester[19]
CREMASTRINE[20]
FLUMEZAPINE[21]
FM1-10[22]
FM1-43[22]
GNF-PF-5618[23]
ISOCLOZAPINE[24]
ISOLOXAPINE[25]
METHACHOLINE[17]
N- (4-Dimethylamino-but-2-ynyl)-N-methyl-acetamide[11]
N-DESMETHYLCLOZAPINE[14]
N-methoxyquinuclidine-3-carboximidoyl chloride[18]
N-methoxyquinuclidine-3-carboximidoyl fluoride[18]
PF-3409409[26]
Propionic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester[19]
SULFOARECOLINE[27]
VU10007[28]
VU10010[28]
XANOMELINE[29]
AgonistCMI-1145[1]
CMI-936[1]
PTAC[30]
AntagonistDiphenidol[5]
Tropicamide[6][7]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice. Mol Pharmacol. 2002 Nov;62(5):1084-93. To Reference
Ref 2Role of the cholinergic muscarinic system in bipolar disorder and related mechanism of action of antipsychotic agents. Mol Psychiatry. 2002;7 Suppl 1:S57-63. To Reference
Ref 3Rab5-dependent trafficking of the m4 muscarinic acetylcholine receptor to the plasma membrane, early endosomes, and multivesicular bodies. J Biol Chem. 2001 Dec 14;276(50):47590-8. Epub 2001 Oct 4. To Reference
Ref 4Neostriatal muscarinic receptor subtypes involved in the generation of tremulous jaw movements in rodents implications for cholinergic involvement in parkinsonism. Life Sci. 2001 Apr 27;68(22-23):2579-84. To Reference
Ref 5Diphenidol-related diamines as novel muscarinic M4 receptor antagonists. Bioorg Med Chem Lett. 2008 May 1;18(9):2972-6. Epub 2008 Mar 23. To Reference
Ref 6The 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. To Reference
Ref 7Zebrafish M2 muscarinic acetylcholine receptor: cloning, pharmacological characterization, expression patterns and roles in embryonic bradycardia. Br J Pharmacol. 2002 Nov;137(6):782-92. To Reference
Ref 8J Med Chem. 1989 May;32(5):1057-62.Synthesis and biological evaluation of [125I]- and [123I]-4-iododexetimide, a potent muscarinic cholinergic receptor antagonist. To Reference
Ref 9J 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. To Reference
Ref 10J 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. To Reference
Ref 11Bioorg. Med. Chem. Lett. 2(8):803-808 (1992) To Reference
Ref 12J 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. To Reference
Ref 13J Med Chem. 1992 Apr 3;35(7):1280-90.Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives. To Reference
Ref 14J 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. To Reference
Ref 15J 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. To Reference
Ref 16J 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. To Reference
Ref 17J Med Chem. 1998 Jun 4;41(12):2047-55.6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors. To Reference
Ref 18Bioorg. Med. Chem. Lett. 2(8):791-796 (1992) To Reference
Ref 19J 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. To Reference
Ref 20J Nat Prod. 2005 Apr;68(4):572-3.Cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata. To Reference
Ref 21J 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. To Reference
Ref 22Bioorg Med Chem Lett. 2008 Jan 15;18(2):825-7. Epub 2007 Nov 17.Design and synthesis of a fluorescent muscarinic antagonist. To Reference
Ref 23J 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. To Reference
Ref 24J Med Chem. 1990 Feb;33(2):809-14.Chloro-substituted, sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents. To Reference
Ref 25J Med Chem. 1981 Sep;24(9):1021-6.Synthesis of clozapine analogues and their affinity for clozapine and spiroperidol binding sites in rat brain. To Reference
Ref 26Bioorg 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. To Reference
Ref 27J Med Chem. 1988 Jul;31(7):1312-6.Heterocyclic muscarinic agonists. Synthesis and biological activity of some bicyclic sulfonium arecoline bioisosteres. To Reference
Ref 28Nat Chem Biol. 2008 Jan;4(1):42-50. Epub 2007 Dec 2.An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission. To Reference
Ref 29Bioorg. Med. Chem. Lett. 2(8):809-814 (1992) To Reference
Ref 30Function 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. To Reference



 

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