Identification

Name
Trimethaphan
Accession Number
DB01116  (APRD00044)
Type
Small Molecule
Groups
Approved, Investigational
Description

A nicotinic antagonist that has been used as a ganglionic blocker in hypertension, as an adjunct to anesthesia, and to induce hypotension during surgery. [PubChem]

Structure
Thumb
Synonyms
  • Thimethaphan
  • Trimetaphan
  • Trimetaphanum
  • Trimethaphan
Product Ingredients
IngredientUNIICASInChI Key
Trimethaphan camsylate8W556014K968-91-7HALWUDBBYKMYPW-STOWLHSFSA-M
International/Other Brands
Arfonad
Categories
UNII
6G8X656T45
CAS number
7187-66-8
Weight
Average: 365.512
Monoisotopic: 365.168759122
Chemical Formula
C22H25N2OS
InChI Key
CHQOEHPMXSHGCL-UHFFFAOYSA-N
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
IUPAC Name
3,5-dibenzyl-4-oxo-8λ⁴-thia-3,5-diazatricyclo[6.3.0.0²,⁶]undecan-8-ylium
SMILES
O=C1N(CC2=CC=CC=C2)C2C[S+]3CCCC3C2N1CC1=CC=CC=C1

Pharmacology

Indication

For the controlled reduction of blood pressure during surgery and in the treatment of hypertensive emergencies.

Pharmacodynamics

Trimethaphan is indicated for production of controlled hypotension during surgery to reduce bleeding into the surgical field and also for rapid reduction of blood pressure in the treatment of hypertensive emergencies, especially in patients with acute dissecting aneurysm, and in the emergency treatment of pulmonary edema in patients with pulmonary hypertension associated with systemic hypertension.

Mechanism of action

Trimethaphan is a ganglionic blocking agent prevents stimulation of postsynaptic receptors by competing with acetylcholine for these receptor sites. Additional effects may include direct peripheral vasodilation and release of histamine. Trimethaphan's hypotensive effect is due to reduction in sympathetic tone and vasodilation, and is primarily postural.

TargetActionsOrganism
ANeuronal acetylcholine receptor subunit alpha-10
antagonist
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
1,10-PhenanthrolineThe therapeutic efficacy of Trimethaphan can be decreased when used in combination with 1,10-Phenanthroline.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Trimethaphan.
AcebutololTrimethaphan may increase the hypotensive activities of Acebutolol.
AcemetacinThe therapeutic efficacy of Trimethaphan can be decreased when used in combination with Acemetacin.
Acetylsalicylic acidThe therapeutic efficacy of Trimethaphan can be decreased when used in combination with Acetylsalicylic acid.
AclidiniumTrimethaphan may increase the anticholinergic activities of Aclidinium.
AgmatineThe risk or severity of adverse effects can be increased when Trimethaphan is combined with Agmatine.
AlcuroniumThe risk or severity of adverse effects can be increased when Trimethaphan is combined with Alcuronium.
AlfentanilThe risk or severity of adverse effects can be increased when Trimethaphan is combined with Alfentanil.
AlfuzosinAlfuzosin may increase the hypotensive activities of Trimethaphan.
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0015248
KEGG Compound
C07174
PubChem Compound
23576
PubChem Substance
46508994
ChemSpider
22044
BindingDB
82545
ChEBI
9728
ChEMBL
CHEMBL1201329
Therapeutic Targets Database
DAP001143
PharmGKB
PA451784
Wikipedia
Trimethaphan
ATC Codes
C02BA01 — Trimetaphan

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableBMI >30 kg/m2 / High Blood Pressure (Hypertension)1
1CompletedDiagnosticBMI >30 kg/m2 / High Blood Pressure (Hypertension) / Progressive autonomic failure / Shy-Drager Syndrome1
1CompletedOtherEndothelial Dysfunction1
1RecruitingBasic ScienceInsulin Resistance1
1RecruitingBasic ScienceIdiopathic orthostatic hypotension / Multiple System Atrophy (MSA) / Supine Hypertension1
1RecruitingOtherHigh Blood Pressure (Hypertension)1
1RecruitingOtherHigh Blood Pressure (Hypertension) / Hypertension,Essential1
Not AvailableCompletedNot AvailableBMI >30 kg/m21
Not AvailableCompletedNot AvailableHigh Blood Pressure (Hypertension) / Progressive autonomic failure1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP3.473Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00665 mg/mLALOGPS
logP4.4ALOGPS
logP2.32ChemAxon
logS-4.8ALOGPS
pKa (Strongest Basic)-2ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area23.55 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity105.43 m3·mol-1ChemAxon
Polarizability40.13 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9641
Blood Brain Barrier+0.9897
Caco-2 permeable-0.5053
P-glycoprotein substrateSubstrate0.6942
P-glycoprotein inhibitor IInhibitor0.6012
P-glycoprotein inhibitor IINon-inhibitor0.6356
Renal organic cation transporterInhibitor0.6812
CYP450 2C9 substrateNon-substrate0.7161
CYP450 2D6 substrateNon-substrate0.6162
CYP450 3A4 substrateNon-substrate0.5152
CYP450 1A2 substrateNon-inhibitor0.5223
CYP450 2C9 inhibitorInhibitor0.5
CYP450 2D6 inhibitorInhibitor0.5134
CYP450 2C19 inhibitorInhibitor0.7361
CYP450 3A4 inhibitorNon-inhibitor0.8947
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.847
Ames testNon AMES toxic0.6511
CarcinogenicityNon-carcinogens0.9545
BiodegradationNot ready biodegradable0.9606
Rat acute toxicity2.3658 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.597
hERG inhibition (predictor II)Inhibitor0.7575
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as thienoimidazolidines. These are heterocyclic compounds containing a thiophene ring fused to an imidazolidine ring. Thiophene is 5-membered ring consisting of four carbon atoms and one sulfur atom. Imidazolidine is 5-membered saturated ring of three carbon atoms, and two nitrogen centers at the 1- and 3-positions.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Thienoimidazolidines
Sub Class
Not Available
Direct Parent
Thienoimidazolidines
Alternative Parents
Imidazolidinones / Benzene and substituted derivatives / Thiophenes / Thiolanes / Ureas / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
show 2 more
Substituents
Thienoimidazolidine / Monocyclic benzene moiety / Imidazolidinone / Benzenoid / Imidazolidine / Thiolane / Thiophene / Carbonic acid derivative / Urea / Azacycle
show 10 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
sulfonium compound (CHEBI:9728)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Receptor binding
Specific Function
Ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding may induce an extensive change in conformation that affects all subunits and leads to opening of an i...
Gene Name
CHRNA10
Uniprot ID
Q9GZZ6
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-10
Molecular Weight
49704.295 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Kurenny DE, Selyanko AA, Derkach VA, Gmiro VE, Skok VI: 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. [PubMed:7963258]
  4. Loiacono R, Stephenson J, Stevenson J, Mitchelson F: Multiple binding sites for nicotine receptor antagonists in inhibiting [3H](-)-nicotine binding in rat cortex. Neuropharmacology. 1993 Sep;32(9):847-53. [PubMed:8232788]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
References
  1. Nakamura K, Koide M, Imanaga T, Ogasawara H, Takahashi M, Yoshikawa M: Prolonged neuromuscular blockade following trimetaphan infusion. A case report and in vitro study of cholinesterase inhibition. Anaesthesia. 1980 Dec;35(12):1202-7. [PubMed:7457791]

Drug created on June 13, 2005 07:24 / Updated on August 02, 2018 07:53