Identification

Name
Thiamylal
Accession Number
DB01154  (APRD00154)
Type
Small Molecule
Groups
Approved, Vet approved
Description

A barbiturate that is administered intravenously for the production of complete anesthesia of short duration, for the induction of general anesthesia, or for inducing a hypnotic state. (From Martindale, The Extra Pharmacopoeia, 30th ed, p919)

Structure
Thumb
Synonyms
  • 5-Allyl-5-(1-methylbutyl)-2-thiobarbituric acid
  • 5-Allyl-5-(1-methylbutyl)-2-thioxodihydro-4,6(1H,5H)-pyrimidinedione
  • 5-Allyl-5-(1-methylbutyl)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione
  • dihydro-5-(1-Methylbutyl)-5-(2-propenyl)-2-thioxo-4,6(1H,5H)-pyrimidinedione
  • Thiamylal
  • Thioseconal
Product Ingredients
IngredientUNIICASInChI Key
Thiamylal sodiumT4L2P3KH7K337-47-3LYZGJWXNOGIVQA-UHFFFAOYSA-M
International/Other Brands
Surital / Thioseconal
Categories
UNII
01T23W89FR
CAS number
77-27-0
Weight
Average: 254.349
Monoisotopic: 254.10889852
Chemical Formula
C12H18N2O2S
InChI Key
XLOMZPUITCYLMJ-UHFFFAOYSA-N
InChI
InChI=1S/C12H18N2O2S/c1-4-6-8(3)12(7-5-2)9(15)13-11(17)14-10(12)16/h5,8H,2,4,6-7H2,1,3H3,(H2,13,14,15,16,17)
IUPAC Name
5-(pentan-2-yl)-5-(prop-2-en-1-yl)-2-sulfanylidene-1,3-diazinane-4,6-dione
SMILES
CCCC(C)C1(CC=C)C(=O)NC(=S)NC1=O

Pharmacology

Indication

Used for the production of complete anaesthesia of short duration, for the induction of general anaesthesia, and for inducing a hypnotic state.

Pharmacodynamics

Thiamylal, a barbiturate, is used in combination with acetaminophen or aspirin and caffeine for its sedative and relaxant effects in the treatment of tension headaches, migraines, and pain. Barbiturates act as nonselective depressants of the central nervous system (CNS), capable of producing all levels of CNS mood alteration from excitation to mild sedation, hypnosis, and deep coma. In sufficiently high therapeutic doses, barbiturates induce anesthesia.

Mechanism of action

Thiamylal binds at a distinct binding site associated with a Cl- ionopore at the GABAA receptor, increasing the duration of time for which the Cl- ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged.

TargetActionsOrganism
AGamma-aminobutyric acid receptor subunit alpha-1
agonist
Human
AATP-sensitive inward rectifier potassium channel 8
inhibitor
Human
AATP-sensitive inward rectifier potassium channel 11
inhibitor
Human
Absorption

Rapidly absorbed (high lipid solubility).

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic.

Route of elimination
Not Available
Half life

Although no studies have been performed on humans, the half-life in cats is 14.3 hours.

Clearance
Not Available
Toxicity

Intravenous LD50 in rat is 51 mg/kg.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be increased when combined with Thiamylal.
(S)-WarfarinThe metabolism of (S)-Warfarin can be increased when combined with Thiamylal.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Thiamylal is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be decreased when it is combined with Thiamylal.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when Thiamylal is combined with 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when Thiamylal is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Thiamylal.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Thiamylal is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Thiamylal is combined with 5-methoxy-N,N-dimethyltryptamine.
6-O-benzylguanineThe serum concentration of 6-O-benzylguanine can be decreased when it is combined with Thiamylal.
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0015285
KEGG Drug
D06106
KEGG Compound
C07846
PubChem Compound
3032285
PubChem Substance
46506261
ChemSpider
2297298
ChEBI
9536
ChEMBL
CHEMBL440
Therapeutic Targets Database
DAP000684
PharmGKB
PA164746997
Wikipedia
Thiamylal
ATC Codes
N05CB01 — Combinations of barbiturates

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)132-133 °CPhysProp
water solubility49.4 mg/L (at 25 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP3.23HANSCH,C ET AL. (1995)
logS-3.46ADME Research, USCD
pKa7.48SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.0506 mg/mLALOGPS
logP3.11ALOGPS
logP2.92ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)7.2ChemAxon
pKa (Strongest Basic)-3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area58.2 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity70.64 m3·mol-1ChemAxon
Polarizability26.75 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.5532
Blood Brain Barrier+0.9582
Caco-2 permeable-0.5361
P-glycoprotein substrateNon-substrate0.5169
P-glycoprotein inhibitor IInhibitor0.5544
P-glycoprotein inhibitor IINon-inhibitor0.9368
Renal organic cation transporterNon-inhibitor0.8887
CYP450 2C9 substrateNon-substrate0.8124
CYP450 2D6 substrateNon-substrate0.8589
CYP450 3A4 substrateNon-substrate0.7011
CYP450 1A2 substrateNon-inhibitor0.7869
CYP450 2C9 inhibitorNon-inhibitor0.5555
CYP450 2D6 inhibitorNon-inhibitor0.9131
CYP450 2C19 inhibitorNon-inhibitor0.6101
CYP450 3A4 inhibitorNon-inhibitor0.8138
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8282
Ames testNon AMES toxic0.6521
CarcinogenicityNon-carcinogens0.9047
BiodegradationNot ready biodegradable0.9974
Rat acute toxicity2.7058 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9781
hERG inhibition (predictor II)Non-inhibitor0.8205
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
GC-MS Spectrum - CI-BGC-MSsplash10-0a4i-0090000000-8766fbc86b0e4f9df12c
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
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as thiobarbituric acid derivatives. These are organic compounds containing a 2-thioxodihydropyrimidine-4,6(1H,5H)-dione skeleton.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazines
Sub Class
Pyrimidines and pyrimidine derivatives
Direct Parent
Thiobarbituric acid derivatives
Alternative Parents
Diazinanes / Thioureas / Carboxylic acids and derivatives / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Thiobarbiturate / 1,3-diazinane / Thiourea / Azacycle / Carboxylic acid derivative / Organic nitrogen compound / Organic oxygen compound / Organopnictogen compound / Organic oxide / Hydrocarbon derivative
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
barbiturates, organosulfur compound (CHEBI:9536)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...
Gene Name
GABRA1
Uniprot ID
P14867
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-1
Molecular Weight
51801.395 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. Sugimura M, Kitayama S, Morita K, Imai Y, Irifune M, Takarada T, Kawahara M, Dohi T: Effects of GABAergic agents on anesthesia induced by halothane, isoflurane, and thiamylal in mice. Pharmacol Biochem Behav. 2002 May;72(1-2):111-6. [PubMed:11900777]
  4. Whiting PJ: The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57. [PubMed:14579514]
  5. Mehta AK, Ticku MK: An update on GABAA receptors. Brain Res Brain Res Rev. 1999 Apr;29(2-3):196-217. [PubMed:10209232]
  6. Yamakura T, Bertaccini E, Trudell JR, Harris RA: Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23-51. [PubMed:11264449]
  7. Krasowski MD, Harrison NL: General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999 Aug 15;55(10):1278-303. [PubMed:10487207]
  8. Grasshoff C, Netzhammer N, Schweizer J, Antkowiak B, Hentschke H: Depression of spinal network activity by thiopental: shift from phasic to tonic GABA(A) receptor-mediated inhibition. Neuropharmacology. 2008 Oct;55(5):793-802. doi: 10.1016/j.neuropharm.2008.06.026. Epub 2008 Jun 21. [PubMed:18619475]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Inward rectifier potassium channel activity
Specific Function
This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their...
Gene Name
KCNJ8
Uniprot ID
Q15842
Uniprot Name
ATP-sensitive inward rectifier potassium channel 8
Molecular Weight
47967.455 Da
References
  1. Eguchi S, Kawano T, Oshita S, Nakajo N: [Effects of propofol and thiamylal on nicorandil induced ATP-sensitive potassium channel activities in cultured rat aortic smooth muscle cells]. Masui. 2005 Apr;54(4):364-9. [PubMed:15852621]
  2. Kawano T, Oshita S, Takahashi A, Tsutsumi Y, Tomiyama Y, Kitahata H, Kuroda Y, Nakaya Y: Molecular mechanisms of the inhibitory effects of propofol and thiamylal on sarcolemmal adenosine triphosphate-sensitive potassium channels. Anesthesiology. 2004 Feb;100(2):338-46. [PubMed:14739809]
  3. Tsutsumi Y, Oshita S, Kitahata H, Kuroda Y, Kawano T, Nakaya Y: Blockade of adenosine triphosphate-sensitive potassium channels by thiamylal in rat ventricular myocytes. Anesthesiology. 2000 Apr;92(4):1154-9. [PubMed:10754636]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated potassium channel activity
Specific Function
This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage ...
Gene Name
KCNJ11
Uniprot ID
Q14654
Uniprot Name
ATP-sensitive inward rectifier potassium channel 11
Molecular Weight
43540.375 Da
References
  1. Kawano T, Oshita S, Takahashi A, Tsutsumi Y, Tomiyama Y, Kitahata H, Kuroda Y, Nakaya Y: Molecular mechanisms of the inhibitory effects of propofol and thiamylal on sarcolemmal adenosine triphosphate-sensitive potassium channels. Anesthesiology. 2004 Feb;100(2):338-46. [PubMed:14739809]
  2. Tsutsumi Y, Oshita S, Kitahata H, Kuroda Y, Kawano T, Nakaya Y: Blockade of adenosine triphosphate-sensitive potassium channels by thiamylal in rat ventricular myocytes. Anesthesiology. 2000 Apr;92(4):1154-9. [PubMed:10754636]
  3. Eguchi S, Kawano T, Oshita S, Nakajo N: [Effects of propofol and thiamylal on nicorandil induced ATP-sensitive potassium channel activities in cultured rat aortic smooth muscle cells]. Masui. 2005 Apr;54(4):364-9. [PubMed:15852621]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Sueyasu M, Fujito K, Shuto H, Mizokoshi T, Kataoka Y, Oishi R: Protein binding and the metabolism of thiamylal enantiomers in vitro. Anesth Analg. 2000 Sep;91(3):736-40. [PubMed:10960410]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Sueyasu M, Fujito K, Shuto H, Mizokoshi T, Kataoka Y, Oishi R: Protein binding and the metabolism of thiamylal enantiomers in vitro. Anesth Analg. 2000 Sep;91(3):736-40. [PubMed:10960410]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Tanaka E, Nakamura T, Inomata S, Honda K: Effects of premedication medicines on the formation of the CYP3A4-dependent metabolite of ropivacaine, 2', 6'-Pipecoloxylidide, on human liver microsomes in vitro. Basic Clin Pharmacol Toxicol. 2006 Feb;98(2):181-3. doi: 10.1111/j.1742-7843.2006.pto_265.x. [PubMed:16445592]

Drug created on June 13, 2005 07:24 / Updated on October 11, 2018 22:27