Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKW3E6B)

• DOT Name: Muscarinic acetylcholine receptor M1 (CHRM1)
• Gene Name: CHRM1
• UniProt ID: ACM1_HUMAN
• PDB ID: 5CXV; 6OIJ; 6WJC; 6ZFZ; 6ZG4; 6ZG9
• Pfam ID: PF00001
• Sequence:
  MNTSAPPAVSPNITVLAPGKGPWQVAFIGITTGLLSLATVTGNLLVLISFKVNTELKTVN
  NYFLLSLACADLIIGTFSMNLYTTYLLMGHWALGTLACDLWLALDYVASNASVMNLLLIS
  FDRYFSVTRPLSYRAKRTPRRAALMIGLAWLVSFVLWAPAILFWQYLVGERTVLAGQCYI
  QFLSQPIITFGTAMAAFYLPVTVMCTLYWRIYRETENRARELAALQGSETPGKGGGSSSS
  SERSQPGAEGSPETPPGRCCRCCRAPRLLQAYSWKEEEEEDEGSMESLTSSEGEEPGSEV
  VIKMPMVDPEAQAPTKQPPRSSPNTVKRPTKKGRDRAGKGQKPRGKEQLAKRKTFSLVKE
  KKAARTLSAILLAFILTWTPYNIMVLVSTFCKDCVPETLWELGYWLCYVNSTINPMCYAL
  CNKAFRDTFRLLLLCRWDKRRWRKIPKRPGSVHRTPSRQC
• 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 Pi turnover.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  PI3K-Akt sig.ling pathway (hsa04151)
  Cholinergic sy.pse (hsa04725)
  Regulation of actin cytoskeleton (hsa04810)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Muscarinic acetylcholine receptors (R-HSA-390648)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gabapentin	DM6T924	Approved	Muscarinic acetylcholine receptor M1 (CHRM1) increases the Sleep disturbances (incl subtypes) ADR of Gabapentin.	[15]
Methylscopolamine	DM5VWOB	Approved	Muscarinic acetylcholine receptor M1 (CHRM1) affects the binding of Methylscopolamine.	[16]
[3H]oxotremorine-M	DM5L7D3	Investigative	Muscarinic acetylcholine receptor M1 (CHRM1) affects the binding of [3H]oxotremorine-M.	[16]
furtrethonium	DM4M3C8	Investigative	Muscarinic acetylcholine receptor M1 (CHRM1) affects the binding of furtrethonium.	[16]
methylfurmethide	DMZ318I	Investigative	Muscarinic acetylcholine receptor M1 (CHRM1) affects the binding of methylfurmethide.	[16]
McN-A-343	DML3AZG	Investigative	Muscarinic acetylcholine receptor M1 (CHRM1) affects the binding of McN-A-343.	[16]

8 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Marinol	DM70IK5	Approved	Marinol affects the binding of Muscarinic acetylcholine receptor M1 (CHRM1).	[1]
Clozapine	DMFC71L	Approved	Clozapine affects the binding of Muscarinic acetylcholine receptor M1 (CHRM1).	[2]
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the binding of Muscarinic acetylcholine receptor M1 (CHRM1).	[3]
Gallamine Triethiodide	DMPO0MS	Approved	Gallamine Triethiodide affects the binding of Muscarinic acetylcholine receptor M1 (CHRM1).	[6]
Pirenzepine	DMP6M1N	Approved	Pirenzepine affects the binding of Muscarinic acetylcholine receptor M1 (CHRM1).	[7]
Staurosporine	DM0E9BR	Investigative	Staurosporine affects the binding of Muscarinic acetylcholine receptor M1 (CHRM1).	[6]
	DM1FBZ7		affects the binding of Muscarinic acetylcholine receptor M1 (CHRM1).	[13]
[3H]QNB	DMC1WHR	Investigative	[3H]QNB affects the binding of Muscarinic acetylcholine receptor M1 (CHRM1).	[14]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetylcholine	DMDF79Z	Approved	Acetylcholine increases the activity of Muscarinic acetylcholine receptor M1 (CHRM1).	[4]
Carbachol	DMX9K8F	Approved	Carbachol increases the activity of Muscarinic acetylcholine receptor M1 (CHRM1).	[4]
Atropine	DMEN6X7	Approved	Atropine decreases the activity of Muscarinic acetylcholine receptor M1 (CHRM1).	[5]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of Muscarinic acetylcholine receptor M1 (CHRM1).	[8]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the activity of Muscarinic acetylcholine receptor M1 (CHRM1).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Muscarinic acetylcholine receptor M1 (CHRM1).	[11]
Paraoxon	DMN4ZKC	Investigative	Paraoxon decreases the expression of Muscarinic acetylcholine receptor M1 (CHRM1).	[12]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Muscarinic acetylcholine receptor M1 (CHRM1).	[10]

References

• [1] Evaluation of first generation synthetic cannabinoids on binding at non-cannabinoid receptors and in a battery of in?vivo assays in mice. Neuropharmacology. 2016 Nov;110(Pt A):143-153. doi: 10.1016/j.neuropharm.2016.07.016. Epub 2016 Jul 20.
• [2] Increasing D2 affinity results in the loss of clozapine's atypical antipsychotic action. Neuroreport. 2002 May 7;13(6):831-5. doi: 10.1097/00001756-200205070-00019.
• [3] No evidence for binding of clozapine, olanzapine and/or haloperidol to selected receptors involved in body weight regulation. Pharmacogenomics J. 2007 Aug;7(4):275-81. doi: 10.1038/sj.tpj.6500418. Epub 2006 Sep 19.
• [4] Regional differences in functional receptor distribution and calcium mobilization in the intact human lens. Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2355-63.
• [5] Assessment of false transmitters as treatments for nerve agent poisoning. Toxicol Lett. 2020 Mar 15;321:21-31. doi: 10.1016/j.toxlet.2019.12.010. Epub 2019 Dec 9.
• [6] 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.
• [7] Fluorescent pirenzepine derivatives as potential bitopic ligands of the human M1 muscarinic receptor. J Med Chem. 2004 Aug 12;47(17):4300-15. doi: 10.1021/jm040800a.
• [8] Androgen receptor-mediated repression of novel target genes. Prostate. 2007 Sep 15;67(13):1371-83. doi: 10.1002/pros.20623.
• [9] Characterization of the potent, selective Nrf2 activator, 3-(pyridin-3-ylsulfonyl)-5-(trifluoromethyl)-2H-chromen-2-one, in cellular and in vivo models of pulmonary oxidative stress. J Pharmacol Exp Ther. 2017 Oct;363(1):114-125.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [12] Effects of paraoxon on neuronal and lymphocytic cholinergic systems. Environ Toxicol Pharmacol. 2011 Jan;31(1):119-28.
• [13] Inhalation by design: novel tertiary amine muscarinic M? receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. J Med Chem. 2011 Oct 13;54(19):6888-904. doi: 10.1021/jm200884j. Epub 2011 Sep 20.
• [14] A snake venom inhibitor to muscarinic acetylcholine receptor (mAChR): isolation and interaction with cloned human mAChR. Arch Biochem Biophys. 2000 May 15;377(2):290-5. doi: 10.1006/abbi.2000.1784.
• [15] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [16] Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mol Pharmacol. 1997 Jul;52(1):172-9.