Details of the Drug

General Information of Drug (ID: DMHF4IQ)

• Drug Name: Trimethaphan
• Synonyms: Thimethaphan; Trimetaphan; Trimetaphanum; Arfonad (TN); Thieno(1',2':1,2)thieno(3,4-d)imidazol-5-ium, decahydro-2-oxo-1,3-bis(phenylmethyl)-(VAN); 1,3-dibenzyl-2-oxodecahydrothieno[1',2':1,2]thieno[3,4-d]imidazol-5-ium

Indication

Disease Entry	ICD 11	Status	REF
Aneurysm	BD51.Z	Approved	[1], [2]
Hypertensive emergency	BA03	Approved	[1], [2]

• Therapeutic Class: Antihypertensive Agents
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 365.5
  Topological Polar Surface Area (xlogp); 3.6
  Rotatable Bond Count (rotbonds); 4
  Hydrogen Bond Donor Count (hbonddonor); 0
  Hydrogen Bond Acceptor Count (hbondacc); 1
• ADMET Property: MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.1118 micromolar/kg/day [3]
• Chemical Identifiers:
  Formula: C22H25N2OS+
  IUPAC Name: 3,5-dibenzyl-8-thionia-3,5-diazatricyclo[6.3.0.02,6]undecan-4-one
  Canonical SMILES: C1CC2C3C(C[S+]2C1)N(C(=O)N3CC4=CC=CC=C4)CC5=CC=CC=C5
  InChI: InChI=1S/C22H25N2OS/c25-22-23(14-17-8-3-1-4-9-17)19-16-26-13-7-12-20(26)21(19)24(22)15-18-10-5-2-6-11-18/h1-6,8-11,19-21H,7,12-16H2/q+1
  InChIKey: CHQOEHPMXSHGCL-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 23576
  ChEBI ID: CHEBI:9728
  CAS Number: 7187-66-8
  DrugBank ID: DB01116
  TTD ID: D0B6CC

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Neuronal acetylcholine receptor alpha-4 (CHRNA4)	TT4H1MQ	ACHA4_HUMAN	Antagonist	[4]

Molecular Expression Atlas of This Drug

• The Studied Disease: Aneurysm
• ICD Disease Classification: BD51.Z

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Neuronal acetylcholine receptor alpha-4 (CHRNA4)	DTT	CHRNA4	3.51E-10	-0.15	-0.61

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Trimethaphan (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Cariprazine	DMJYDVK	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Cariprazine.	Bipolar disorder [6A60]	[13]
Atracurium	DM42HXN	Moderate	Additive neuromuscular blocking effects by the combination of Trimethaphan and Atracurium.	Corneal disease [9A76-9A78]	[14]
Mivacurium	DM473VD	Moderate	Additive neuromuscular blocking effects by the combination of Trimethaphan and Mivacurium.	Corneal disease [9A76-9A78]	[14]
Pancuronium	DMB0VY8	Moderate	Additive neuromuscular blocking effects by the combination of Trimethaphan and Pancuronium.	Corneal disease [9A76-9A78]	[14]
Isocarboxazid	DMAF1NB	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Isocarboxazid.	Depression [6A70-6A7Z]	[15]
OPC-34712	DMHG57U	Moderate	Additive hypotensive effects by the combination of Trimethaphan and OPC-34712.	Depression [6A70-6A7Z]	[13]
Procarbazine	DMIK367	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Procarbazine.	Hodgkin lymphoma [2B30]	[15]
ITI-007	DMUQ1DO	Moderate	Additive hypotensive effects by the combination of Trimethaphan and ITI-007.	Insomnia [7A00-7A0Z]	[13]
Ozanimod	DMT6AM2	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Ozanimod.	Multiple sclerosis [8A40]	[15]
Safinamide	DM0YWJC	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Safinamide.	Parkinsonism [8A00]	[15]
Rasagiline	DM3WKQ4	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Rasagiline.	Parkinsonism [8A00]	[15]
Quetiapine	DM1N62C	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Quetiapine.	Schizophrenia [6A20]	[13]
Aripiprazole	DM3NUMH	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Aripiprazole.	Schizophrenia [6A20]	[13]
Iloperidone	DM6AUFY	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Iloperidone.	Schizophrenia [6A20]	[13]
Paliperidone	DM7NPJS	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Paliperidone.	Schizophrenia [6A20]	[13]
Molindone	DMAH70G	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Molindone.	Schizophrenia [6A20]	[13]
Thiothixene	DMDINC4	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Thiothixene.	Schizophrenia [6A20]	[13]
Amisulpride	DMSJVAM	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Amisulpride.	Schizophrenia [6A20]	[13]
Asenapine	DMSQZE2	Moderate	Additive hypotensive effects by the combination of Trimethaphan and Asenapine.	Schizophrenia [6A20]	[13]

References

• [1] Drug information of Trimethaphan, 2008. eduDrugs.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [4] Mechanism of long-lasting block of ganglion nicotinic receptors by mono-ammonium compounds with long aliphatic chain. J Auton Nerv Syst. 1994 Aug;48(3):231-40.
• [5] Nicotinic and nonnicotinic receptor-mediated actions of vinblastine. Proc Soc Exp Biol Med. 1993 Jul;203(3):372-6.
• [6] Epibatidine isomers and analogues: structure-activity relationships. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5493-7.
• [7] The nicotinic acetylcholine receptor agonist ABT-594 increases FGF-2 expression in various rat brain regions. Neuroreport. 1999 Dec 16;10(18):3909-13.
• [8] (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT 418): a novel cholinergic ligand with cognition-enhancing and anxiolytic activities: II. In vivo characterization. J Pharmacol Exp Ther. 1994 Jul;270(1):319-28.
• [9] 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.
• [10] Whiting PJ: The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57.
• [11] Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation. J Med Chem. 2010 Jun 24;53(12):4731-48.
• [12] Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers. Bioorg Med Chem. 2007 May 15;15(10):3368-72.
• [13] Product Information. Clozaril (clozapine). Novartis Pharmaceuticals, East Hanover, NJ.
• [14] Multum Information Services, Inc. Expert Review Panel.
• [15] Product Information. Marplan (isocarboxazid) Roche Laboratories, Nutley, NJ.