General Information of Drug Therapeutic Target (DTT) (ID: TTOXS3C)

DTT Name Muscarinic acetylcholine receptor (CHRM)
Gene Name CHRM
DTT Type
Successful target
[1]
UniProt ID
NOUNIPROTAC
TTD ID
T09130
Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through theaction of G proteins. Primary transducing effect is Pi turnover.
KEGG Pathway
Calcium signaling pathway (hsa04020 )
cAMP signaling pathway (hsa04024 )
Neuroactive ligand-receptor interaction (hsa04080 )
PI3K-Akt signaling pathway (hsa04151 )
Cholinergic synapse (hsa04725 )
Regulation of actin cytoskeleton (hsa04810 )
Reactome Pathway
Acetylcholine regulates insulin secretion (R-HSA-399997 )
G alpha (q) signalling events (R-HSA-416476 )
Muscarinic acetylcholine receptors (R-HSA-390648 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
10 Approved Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Acetylcholine DMDF79Z Cataract 9B10 Approved [2]
Clidinium DMUMQZ0 Abdominal stomach pain DD91.4 Approved [3]
Darifenacin DMWXLYZ Overactive bladder GC50.0 Approved [4]
Incruse Ellipta DM32GSJ Chronic obstructive pulmonary disease CA22 Approved [5]
Isopropamide iodide DMQYV60 Allergic rhinitis CA08.0 Approved [1]
Methylscopolamine DM5VWOB Peptic ulcer DA61 Approved [6]
Oxybutynin hydrochloride DMF2KLU Urinary incontinence MF50.2 Approved [7]
Revefenacin DMMP5SI Chronic obstructive pulmonary disease CA22 Approved [8]
Scopolamine DMOM8AL Addictive disorder 6C50-6C5Z Approved [9]
Tiotropium DMFDC0Q Chronic obstructive pulmonary disease CA22 Approved [10]
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⏷ Show the Full List of 10 Approved Drug(s)
10 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
SUN-101 DMXNZQK Chronic obstructive pulmonary disease CA22 Phase 3 [11]
THVD-201 DM3PA8H Overactive bladder GC50.0 Phase 3 [12]
APD-515 DM9LZ0M Xerostomia DA02.1 Phase 2 [13]
AZD-2115 DMGQSVX Chronic obstructive pulmonary disease CA22 Phase 2 [14]
AZD-8683 DMLXFM6 Chronic obstructive pulmonary disease CA22 Phase 2 [15]
AZD-9164 DMVKPEZ Chronic obstructive pulmonary disease CA22 Phase 2 [16]
EP-101 DM69NF1 Chronic obstructive pulmonary disease CA22 Phase 2 [17]
QAX-028 DMXY0H2 Chronic obstructive pulmonary disease CA22 Phase 2 [18]
SMP-986 DMTJOQX Overactive bladder GC50.0 Phase 2 [19]
PUR0200 DMX5LB7 Chronic obstructive pulmonary disease CA22 Phase 1 [20]
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⏷ Show the Full List of 10 Clinical Trial Drug(s)
5 Discontinued Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Telenzepine DM6PVWS Chronic obstructive pulmonary disease CA22 Discontinued in Preregistration [21]
Milameline DMPCY8K Cognitive impairment 6D71 Discontinued in Phase 3 [22]
Terflavoxate DM4K3P9 Urinary incontinence MF50.2 Discontinued in Phase 2 [23]
A-72055 DM7FI3S Alzheimer disease 8A20 Terminated [24]
U-80816 DMGUMWP Amnesia MB21.1 Terminated [25]
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61 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
AF-DX-384 DMNY8H7 Discovery agent N.A. Investigative [26]
Alexa-488-telenzepine DM83CDK Discovery agent N.A. Investigative [27]
arecaidine propargyl ester DMSA6IY Discovery agent N.A. Investigative [28]
benzoquinazolinone 12 DMMKBFN Discovery agent N.A. Investigative [29]
BODIPY-pirenzepine DMY7CN3 Discovery agent N.A. Investigative [30]
brucine DM50RUD Discovery agent N.A. Investigative [31]
C7/3-phth DM7MNOX Discovery agent N.A. Investigative [32]
Cy3B-telenzepine DMBKTHI Discovery agent N.A. Investigative [27]
DS-AH-14 DMZGWQA Asthma CA23 Investigative [33]
Duo3 DMUKPO3 Discovery agent N.A. Investigative [34]
furtrethonium DM4M3C8 Discovery agent N.A. Investigative [28]
Go7874 DMS91OR Discovery agent N.A. Investigative [35]
guanylpirenzepine DMOUQLB Discovery agent N.A. Investigative [36]
hexahydrodifenidol DMH25OD Discovery agent N.A. Investigative [37]
hexahydrosiladifenidol DM6UAV7 Discovery agent N.A. Investigative [37]
iperoxo DM6OHVU Discovery agent N.A. Investigative [38]
KT 5823 DMOBYU3 Discovery agent N.A. Investigative [35]
levetimide DMPYSIT Discovery agent N.A. Investigative [3]
lithocholylcholine DME76CQ Discovery agent N.A. Investigative [6]
LY2033298 DMVHQGF Discovery agent N.A. Investigative [39]
LY2119620 DM4IELQ Discovery agent N.A. Investigative [40]
LY593093 DMQE89J Discovery agent N.A. Investigative [41]
McN-A-343 DML3AZG Discovery agent N.A. Investigative [42]
methylfurmethide DMZ318I Discovery agent N.A. Investigative [28]
ML169 DMPB7EL Discovery agent N.A. Investigative [43]
ML375 DMXJASC Discovery agent N.A. Investigative [44]
ML380 DMQROC3 Discovery agent N.A. Investigative [45]
ML381 DMKCIP0 Discovery agent N.A. Investigative [46]
N-benzyl brucine DMOQMEU Discovery agent N.A. Investigative [31]
N-chloromethyl-brucine DM6VEON Discovery agent N.A. Investigative [31]
NNC 11-1314 DMSQ4TL Discovery agent N.A. Investigative [47]
NNC 11-1585 DMMX19B Discovery agent N.A. Investigative [47]
NNC 11-1607 DMZJSWI Discovery agent N.A. Investigative [47]
p-F-HHSiD DM9CV6S Discovery agent N.A. Investigative [48]
pentylthio-TZTP DMD8NHB Discovery agent N.A. Investigative [28]
RBx-343E48F0 DMNEK79 Chronic obstructive pulmonary disease CA22 Investigative [15]
silahexocyclium DM4VDMP Discovery agent N.A. Investigative [37]
thiochrome DML4TQ5 Discovery agent N.A. Investigative [2]
THRX160209 DMY07CA Discovery agent N.A. Investigative [49]
tripitramine DMWZ5FB Discovery agent N.A. Investigative [50]
UH-AH 37 DMT5UMG Discovery agent N.A. Investigative [51]
vinburnine DMO4GBK Discovery agent N.A. Investigative [28]
VU0010010 DMXD3T7 Discovery agent N.A. Investigative [52]
VU0029767 DMRNLGW Discovery agent N.A. Investigative [53]
VU0090157 DMGFTVI Discovery agent N.A. Investigative [53]
VU0152099 DM1UAQT Discovery agent N.A. Investigative [54]
VU0152100 DM04HUC Discovery agent N.A. Investigative [54]
VU0255035 DMRKE6W Discovery agent N.A. Investigative [55]
W-84 DMMBI9Y Discovery agent N.A. Investigative [56]
WDuo3 DMWU5PK Discovery agent N.A. Investigative [56]
WIN 51,708 DMY5LOB Discovery agent N.A. Investigative [57]
WIN 62,577 DMGOQY2 Discovery agent N.A. Investigative [57]
[11C]butylthio-TZTP DMQP03A Discovery agent N.A. Investigative [58]
[11C]xanomeline DM742L9 Discovery agent N.A. Investigative [58]
[18F](R,R)-quinuclidinyl-4-fluoromethyl-benzilate DMZJQC0 Discovery agent N.A. Investigative [59]
[18F]FP-TZTP DMM2YU9 Discovery agent N.A. Investigative [60]
[3H]4NMPB DM5SWI1 Discovery agent N.A. Investigative [61]
[3H]dimethyl-W84 DMBWAIE Discovery agent N.A. Investigative [56]
[3H]oxotremorine-M DM5L7D3 Discovery agent N.A. Investigative [28]
[3H]pirenzepine DMAMD5H Discovery agent N.A. Investigative [62]
[3H]QNB DMC1WHR Discovery agent N.A. Investigative [63]
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⏷ Show the Full List of 61 Investigative Drug(s)

References

1 Competitive and non-competitive antagonism exhibited by 'selective' antagonists at atrial and ileal muscarinic receptor subtypes. Br J Pharmacol. 1987 Apr;90(4):701-7.
2 Thiochrome enhances acetylcholine affinity at muscarinic M4 receptors: receptor subtype selectivity via cooperativity rather than affinity. Mol Pharmacol. 2004 Jan;65(1):257-66.
3 Pharmacological comparison of the cloned human and rat M2 muscarinic receptor genes expressed in the murine fibroblast (B82) cell line. J Pharmacol Exp Ther. 1998 Feb;284(2):500-7.
4 Characterisation of [3H]-darifenacin as a novel radioligand for the study of muscarinic M3 receptors. J Recept Signal Transduct Res. 1997 Jan-May;17(1-3):177-84.
5 Clinical pipeline report, company report or official report of GlaxoSmithKline.
6 Lithocholylcholine, a bile acid/acetylcholine hybrid, is a muscarinic receptor antagonist. J Pharmacol Exp Ther. 2002 Oct;303(1):29-35.
7 Effects of propiverine hydrochloride (propiverine) on the muscarinic receptor binding affinity in guinea pig tissues and on salivation in conscious dogs. Nihon Yakurigaku Zasshi. 1999 Mar;113(3):157-66.
8 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
9 The amygdala modulates morphine-induced state-dependent memory retrieval via muscarinic acetylcholine receptors. Neuroscience. 2009 May 5;160(2):255-63.
10 Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70.
11 Long-acting bronchodilators in COPD: Where are we now and where are we going Breathe 06/2014; 10(2):110-120.
12 Future therapies: Early trials and basic science. Can Urol Assoc J. 2013 Sep-Oct; 7(9-10 Suppl 4): S179-S180.
13 Clinical pipeline report, company report or official report of Acacia Pharma.
14 Evaluation of WO-2012085582 and WO-2012085583 two identified MABAs: backups to AZD-2115. Expert Opin Ther Pat. 2012 Nov;22(11):1377-83.
15 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. (Target id: 17).
16 The discovery of AZD9164, a novel muscarinic M3 antagonist. Bioorg Med Chem Lett. 2011 Dec 15;21(24):7440-6.
17 Long-acting muscarinic receptor antagonists for the treatment of respiratory disease. Pulm Pharmacol Ther. 2013 Jun;26(3):307-17.
18 EP patent application no. 2398798, Triazolopyridine derivatives as p38 map kinase inhibitors.
19 DUAL INHIBITION OF Na+-CHANNEL AND MUSCARINIC RECEPTORS BY SMP-986 EFFICIENTLY IMPROVED VOIDING FUNCTION COMPARED TO ANTI-MUSCARINIC AGENTS IN TWO CONSCIOUS RAT MODELS OF DETRUSOR OVERACTIVITY. The Journal of Urology Volume 179, Issue 4, Supplement, April 2008, Pages 129.
20 Clinical pipeline report, company report or official report of pulmatrix pipeline.
21 The existence of stable enantiomers of telenzepine and their stereoselective interaction with muscarinic receptor subtypes. Mol Pharmacol. 1989 Apr;35(4):477-83.
22 Milameline (CI-979/RU35926): a muscarinic receptor agonist with cognition-activating properties: biochemical and in vivo characterization. J Pharmacol Exp Ther. 1999 Nov;291(2):812-22.
23 Effects of terflavoxate on stimulated contractions of urinary bladder in vitro. Arzneimittelforschung. 1993 Feb;43(2):122-8.
24 US patent application no. 2011,0020,423, Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation.
25 U-80816: A novel partial muscarinic agonist. Drug Development Research Volume 24, Issue 1, pages 53-66, 1991.
26 Binding of [3H]AF-DX 384 to cloned and native muscarinic receptors. J Pharmacol Exp Ther. 1991 Nov;259(2):601-7.
27 Formation and dissociation of M1 muscarinic receptor dimers seen by total internal reflection fluorescence imaging of single molecules. Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2693-8.
28 Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mol Pharmacol. 1997 Jul;52(1):172-9.
29 Mechanistic insights into allosteric structure-function relationships at the M1 muscarinic acetylcholine receptor. J Biol Chem. 2014 Nov 28;289(48):33701-11.
30 Pirenzepine promotes the dimerization of muscarinic M1 receptors through a three-step binding process. J Biol Chem. 2009 Jul 17;284(29):19533-43.
31 Subtype-selective positive cooperative interactions between brucine analogues and acetylcholine at muscarinic receptors: radioligand binding studies. Mol Pharmacol. 1998 Mar;53(3):573-89.
32 Characterization of the subtype selectivity of the allosteric modulator heptane-1,7-bis-(dimethyl-3'-phthalimidopropyl) ammonium bromide (C7/3-phth) at cloned muscarinic acetylcholine receptors. Biochem Pharmacol. 1999 Jan 15;57(2):171-9.
33 US patent application no. 5,446,057, Substituted tetrahydropyridine and piperidine carboxylic acids as muscarinic antagonists.
34 Atypical muscarinic allosteric modulation: cooperativity between modulators and their atypical binding topology in muscarinic M2 and M2/M5 chimeric... Mol Pharmacol. 2005 Dec;68(6):1597-610.
35 Allosteric interactions of staurosporine and other indolocarbazoles with N-[methyl-(3)H]scopolamine and acetylcholine at muscarinic receptor subtypes: identification of a second allosteric site. Mol Pharmacol. 2000 Jul;58(1):194-207.
36 Subtypes of muscarinic receptors in rat duodenum: a comparison with rabbit vas deferens, rat atria, guinea-pig ileum and gallbladder by using imperialine. Gen Pharmacol. 1999 Apr;32(4):505-11.
37 Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells. Mol Pharmacol. 1989 Apr;35(4):469-76.
38 Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor. Br J Pharmacol. 2013 May;169(2):357-70.
39 Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10978-83.
40 Characterization of the novel positive allosteric modulator, LY2119620, at the muscarinic M(2) and M(4) receptors. Mol Pharmacol. 2014 Jul;86(1):106-15.
41 Pharmacological characterization of LY593093, an M1 muscarinic acetylcholine receptor-selective partial orthosteric agonist. J Pharmacol Exp Ther. 2011 Aug;338(2):622-32.
42 Pharmacological characterization of the M1 muscarinic receptors expressed in murine fibroblast B82 cells. J Pharmacol Exp Ther. 1989 Feb;248(2):661-70.
43 Targeting selective activation of M(1) for the treatment of Alzheimer's disease: further chemical optimization and pharmacological characterization of the M(1) positive allosteric modulator ML169. ACS Chem Neurosci. 2012 Nov 21;3(11):884-95.
44 Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). J Med Chem. 2013 Nov 27;56(22):9351-5.
45 Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380). J Med Chem. 2014 Sep 25;57(18):7804-10.
46 Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe. ChemMedChem. 2014 Aug;9(8):1677-82.
47 Synthesis and pharmacological evaluation of dimeric muscarinic acetylcholine receptor agonists. J Pharmacol Exp Ther. 2001 Sep;298(3):1260-8.
48 Stimulation of cyclic AMP accumulation and phosphoinositide hydrolysis by M3 muscarinic receptors in the rat peripheral lung. Biochem Pharmacol. 1996 Aug 23;52(4):643-58.
49 A novel multivalent ligand that bridges the allosteric and orthosteric binding sites of the M2 muscarinic receptor. Mol Pharmacol. 2007 Aug;72(2):291-302.
50 Binding profile of the selective muscarinic receptor antagonist tripitramine. Eur J Pharmacol. 1994 Aug 16;268(3):459-62.
51 Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists. Eur J Pharmacol. 1998 May 22;349(2-3):285-92.
52 Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends Pharmacol Sci. 2009 Mar;30(3):148-55.
53 Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of activity. Mol Pharmacol. 2009 Mar;75(3):577-88.
54 Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats. J Pharmacol Exp Ther. 2008 Dec;327(3):941-53.
55 A novel selective muscarinic acetylcholine receptor subtype 1 antagonist reduces seizures without impairing hippocampus-dependent learning. Mol Pharmacol. 2009 Aug;76(2):356-68.
56 Interactions of orthosteric and allosteric ligands with [3H]dimethyl-W84 at the common allosteric site of muscarinic M2 receptors. Mol Pharmacol. 2003 Jul;64(1):180-90.
57 Analogs of WIN 62,577 define a second allosteric site on muscarinic receptors. Mol Pharmacol. 2002 Dec;62(6):1492-505.
58 PET study of the M1-agonists [11C]xanomeline and [11C]butylthio-TZTP in monkey and man. Dementia. 1996 Jul-Aug;7(4):187-95.
59 In vivo muscarinic binding selectivity of (R,S)- and (R,R)-[18F]-fluoromethyl QNB. Bioorg Med Chem. 1997 Aug;5(8):1555-67.
60 Regional brain uptake of the muscarinic ligand, [18F]FP-TZTP, is greatly decreased in M2 receptor knockout mice but not in M1, M3 and M4 receptor knockout mice. Neuropharmacology. 2003 Apr;44(5):653-61.
61 Cloned M1 muscarinic receptors mediate both adenylate cyclase inhibition and phosphoinositide turnover. EMBO J. 1988 Oct;7(10):3031-5.
62 [3H]Pirenzepine identifies putative M1 muscarinic receptors in human stellate ganglia. Brain Res. 1984 Jan 2;290(1):179-82.
63 Interaction of anandamide with the M(1) and M(4) muscarinic acetylcholine receptors. Brain Res. 2001 Oct 5;915(1):70-8.