Identification

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Name
Pentoxyverine
Accession Number
DB11186
Type
Small Molecule
Groups
Approved, Investigational
Description

Pentoxyverine, also referred to as carbetapentane, is a non-opioid central acting antitussive with antimuscarinic, anticonvulsant 4, and local anesthetic properties. It is an active ingredient in over-the-counter cough suppressants in combination with guaifenesin and H1-receptor antagonists 1. Pentoxyverine acts on sigma-1 receptors, as well as kappa and mu-opioid receptors.

Structure
Thumb
Synonyms
  • Carbetapentane
Product Ingredients
IngredientUNIICASInChI Key
Pentoxyverine citrate4SH0MFJ5HJ23142-01-0AKJDEXBCRLOVTH-UHFFFAOYSA-N
Pentoxyverine tannate23K1F351T71406-98-0LILZIIRVLKMYCP-HBNMXAOGSA-N
Product Images
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Vicks Cough Syrup New ImprovedPentoxyverine citrate (15 mg) + Ephedrine (8 mg) + Guaifenesin (200 mg)SyrupOralRichardson Vicks, Division Of The Procter & Gamble Company1983-12-312000-07-28Canada
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
C-Tanna 12D SuspensionPentoxyverine tannate (30 mg/5mL) + Mepyramine tannate (30 mg/5mL) + Phenylephrine tannate (5 mg/5mL)SuspensionOralPrasco, Laboratories2006-01-012008-10-31Us
CarbatussPentoxyverine citrate (20 mg/5mL) + Guaifenesin (100 mg/5mL) + Phenylephrine hydrochloride (10 mg/5mL)LiquidOralGm Pharmaceuticals2000-11-012007-11-01Us
CarbetaplexPentoxyverine citrate (20 mg/5mL) + Guaifenesin (100 mg/5mL) + Phenylephrine hydrochloride (15 mg/5mL)LiquidOralBreckenridge Pharmaceutical, Inc.2004-04-012009-09-30Us51991 08320180906 25352 173omie
CorzallPentoxyverine citrate (20 mg/5mL) + Pseudoephedrine hydrochloride (30 mg/5mL)LiquidOralHawthorn Pharmaceuticals, Inc.2009-08-272011-08-26Us
Corzall PEPentoxyverine citrate (20 mg/5mL) + Dexchlorpheniramine maleate (1 mg/5mL) + Phenylephrine hydrochloride (10 mg/5mL)LiquidOralHawthorn Pharmaceuticals, Inc.2010-09-222011-08-26Us
Corzall PlusPentoxyverine citrate (20 mg/5mL) + Mepyramine maleate (7.5 mg/5mL) + Pseudoephedrine hydrochloride (30 mg/5mL)LiquidOralHawthorn Pharmaceuticals, Inc.2009-08-282011-08-26Us
ExallPentoxyverine citrate (10 mg/5mL) + Guaifenesin (100 mg/5mL)LiquidOralHawthorn Pharmaceuticals, Inc.2009-08-242011-08-26Us
Exall DPentoxyverine citrate (10 mg/5mL) + Guaifenesin (100 mg/5mL) + Pseudoephedrine hydrochloride (30 mg/5mL)LiquidOralHawthorn Pharmaceuticals, Inc.2009-11-092011-08-26Us
EXPECTUSS LiquidPentoxyverine citrate (20 mg/5mL) + Guaifenesin (75 mg/5mL)LiquidOralCenturion Labs2009-11-302016-05-02Us
Phenylephrine Carbetapentane Potassium GuaiacolsulfonatePentoxyverine (20 mg/5mL) + Phenylephrine (10 mg/5mL) + Potassium Guaiacolsulfonate (100 mg/5mL)LiquidOralRiver's Edge Pharmaceuticals, LLC2010-03-012010-11-20Us
Categories
UNII
32C726X12W
CAS number
77-23-6
Weight
Average: 333.472
Monoisotopic: 333.230393862
Chemical Formula
C20H31NO3
InChI Key
CFJMRBQWBDQYMK-UHFFFAOYSA-N
InChI
InChI=1S/C20H31NO3/c1-3-21(4-2)14-15-23-16-17-24-19(22)20(12-8-9-13-20)18-10-6-5-7-11-18/h5-7,10-11H,3-4,8-9,12-17H2,1-2H3
IUPAC Name
2-[2-(diethylamino)ethoxy]ethyl 1-phenylcyclopentane-1-carboxylate
SMILES
CCN(CC)CCOCCOC(=O)C1(CCCC1)C1=CC=CC=C1

Pharmacology

Indication

Indicated as a cough suppressant to relieve cough caused by the common cold, flu, bronchitis, and sinusitis 1.

Pharmacodynamics

Pentoxyverine induces an antitussive action. In animal studies, intraperitoneal administration of pentoxyverine inhibited citric-acid-induced cough in guinea-pigs in vivo 2. Some mice and rat studies suggest that pentoxyverine may also exert anticonvulsant activities without inducing a protective effect from NMDA-induced lethality 4,5. Protective effects against maximal electroshock-induced seizures in a dose-related fashion was also observed following either intraperitoneal or oral administration 5. In hERG-transfected cells, pentoxyverine inhibited the outward current of the hERG ion channel with half-maximal inhibition concentrations (IC50) of 3.0 µM 3. In rats receiving intrathecal administration, pentoxyverine exhibited dose-dependent spinal blockade with a more sensory-selective action over motor blockade 6. It induced a spinal blockade with a more sensory/nociceptive-selective action over motor blockade compared to lidocaine 6.

Mechanism of action

While the mechanism of antitussive action of pentoxyverine is not fully understood, it is thought to be mediated via sigma-1 receptors expressed in the central nervous system 1. Pentoxyverine acts as an agonist at sigma receptors with the Ki of 75±28 nM, as demonstrated in a competitive binding assay 2. The function of sigma receptors on cough suppressant activities is unclear, however these receptors are highly expressed in the nucleus tractus solitarius (NTS) of the brainstem where the afferent fibres first synapse 2. NTS is located very close to the cough centre in the brainstem thus may function as a ‘gate' for the cough reflex and allow sigma-1 receptor agonists to modulate afferent activity prior to reaching the cough center 2. It is suggested that highly lipophilic sigma-1 agonists may penetrate the CNS following systemic administration. When administered as aerosols, sigma-1 receptor agonists may temporarily act in the periphery to modulate cough by acting activate sigma receptors expressed in the lungs 2. However there is limited evidence of peripheral localization of the sigma agonists following aerosol administration and the ruling out of systemic exposure 2. The local anesthesia action of pentoxyverine may occur through inhibition of voltage-gated Na(+) currents 6.

TargetActionsOrganism
ASigma non-opioid intracellular receptor 1
agonist
Humans
UPotassium voltage-gated channel subfamily H member 2
inhibitor
Humans
UVoltage-gated sodium channel alpha subunit
inhibitor
Humans
UKappa-type opioid receptor
agonist
Humans
UMu-type opioid receptor
antagonist
Humans
Absorption

In humans, maximum plasma concentrations are achieved 1.2 hours after oral dosing 1.

Volume of distribution

No pharmacokinetic data available.

Protein binding

No pharmacokinetic data available.

Metabolism

No pharmacokinetic data available.

Route of elimination

No pharmacokinetic data available.

Half life

The half-life is 2.3 hours following oral dosing 1.

Clearance

No pharmacokinetic data available.

Toxicity

Acute oral LD50 is 810 mg/kg in rat and 230 mg/kg in mouse MSDS.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

References

General References
  1. Dicpinigaitis PV, Morice AH, Birring SS, McGarvey L, Smith JA, Canning BJ, Page CP: Antitussive drugs--past, present, and future. Pharmacol Rev. 2014 Mar 26;66(2):468-512. doi: 10.1124/pr.111.005116. Print 2014. [PubMed:24671376]
  2. Brown C, Fezoui M, Selig WM, Schwartz CE, Ellis JL: Antitussive activity of sigma-1 receptor agonists in the guinea-pig. Br J Pharmacol. 2004 Jan;141(2):233-40. doi: 10.1038/sj.bjp.0705605. Epub 2003 Dec 22. [PubMed:14691051]
  3. Deisemann H, Ahrens N, Schlobohm I, Kirchhoff C, Netzer R, Moller C: Effects of common antitussive drugs on the hERG potassium channel current. J Cardiovasc Pharmacol. 2008 Dec;52(6):494-9. doi: 10.1097/FJC.0b013e31818eec8d. [PubMed:19034038]
  4. Tortella FC, Musacchio JM: Dextromethorphan and carbetapentane: centrally acting non-opioid antitussive agents with novel anticonvulsant properties. Brain Res. 1986 Sep 24;383(1-2):314-8. [PubMed:3768695]
  5. Leander JD: Evaluation of dextromethorphan and carbetapentane as anticonvulsants and N-methyl-D-aspartic acid antagonists in mice. Epilepsy Res. 1989 Jul-Aug;4(1):28-33. [PubMed:2666123]
  6. Leung YM, Tzeng JI, Kuo CS, Chen YW, Chu CC, Wang JJ: The use of carbetapentane for spinal anesthesia and use-dependent block of sodium currents. Eur J Pharmacol. 2013 Aug 15;714(1-3):366-72. doi: 10.1016/j.ejphar.2013.07.013. Epub 2013 Jul 16. [PubMed:23872380]
External Links
PubChem Compound
2562
PubChem Substance
347827938
ChemSpider
2464
BindingDB
94507
ChEBI
94484
ChEMBL
CHEMBL73234
Wikipedia
Pentoxyverine
ATC Codes
R05DB05 — Pentoxyverine
MSDS
Download (77.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SuspensionOral
LiquidOral
TabletOral
SyrupOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)90-95MSDS
water solubility1 g/10 mlMSDS
Predicted Properties
PropertyValueSource
Water Solubility0.0231 mg/mLALOGPS
logP4.16ALOGPS
logP3.97ChemAxon
logS-4.2ALOGPS
pKa (Strongest Basic)9.41ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area38.77 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity97.17 m3·mol-1ChemAxon
Polarizability39.25 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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 benzene and substituted derivatives. These are aromatic compounds containing one monocyclic ring system consisting of benzene.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Not Available
Direct Parent
Benzene and substituted derivatives
Alternative Parents
Trialkylamines / Carboxylic acid esters / Amino acids and derivatives / Monocarboxylic acids and derivatives / Dialkyl ethers / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Monocyclic benzene moiety / Amino acid or derivatives / Carboxylic acid ester / Tertiary amine / Tertiary aliphatic amine / Carboxylic acid derivative / Dialkyl ether / Ether / Monocarboxylic acid or derivatives / Organic oxygen compound
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
Curator comments
Competitive binding assays finding report the Ki to be 75±28 nM.
General Function
Opioid receptor activity
Specific Function
Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma m...
Gene Name
SIGMAR1
Uniprot ID
Q99720
Uniprot Name
Sigma non-opioid intracellular receptor 1
Molecular Weight
25127.52 Da
References
  1. Brown C, Fezoui M, Selig WM, Schwartz CE, Ellis JL: Antitussive activity of sigma-1 receptor agonists in the guinea-pig. Br J Pharmacol. 2004 Jan;141(2):233-40. doi: 10.1038/sj.bjp.0705605. Epub 2003 Dec 22. [PubMed:14691051]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
Molecular Weight
126653.52 Da
References
  1. Deisemann H, Ahrens N, Schlobohm I, Kirchhoff C, Netzer R, Moller C: Effects of common antitussive drugs on the hERG potassium channel current. J Cardiovasc Pharmacol. 2008 Dec;52(6):494-9. doi: 10.1097/FJC.0b013e31818eec8d. [PubMed:19034038]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Voltage-gated sodium channel activity
Specific Function
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a...

Components:
References
  1. Leung YM, Tzeng JI, Kuo CS, Chen YW, Chu CC, Wang JJ: The use of carbetapentane for spinal anesthesia and use-dependent block of sodium currents. Eur J Pharmacol. 2013 Aug 15;714(1-3):366-72. doi: 10.1016/j.ejphar.2013.07.013. Epub 2013 Jul 16. [PubMed:23872380]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synt...
Gene Name
OPRK1
Uniprot ID
P41145
Uniprot Name
Kappa-type opioid receptor
Molecular Weight
42644.665 Da
References
  1. Kobayashi T, Ikeda K, Ichikawa T, Togashi S, Kumanishi T: Effects of sigma ligands on the cloned mu-, delta- and kappa-opioid receptors co-expressed with G-protein-activated K+ (GIRK) channel in Xenopus oocytes. Br J Pharmacol. 1996 Sep;119(1):73-80. [PubMed:8872359]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Voltage-gated calcium channel activity
Specific Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
Molecular Weight
44778.855 Da
References
  1. Kobayashi T, Ikeda K, Ichikawa T, Togashi S, Kumanishi T: Effects of sigma ligands on the cloned mu-, delta- and kappa-opioid receptors co-expressed with G-protein-activated K+ (GIRK) channel in Xenopus oocytes. Br J Pharmacol. 1996 Sep;119(1):73-80. [PubMed:8872359]

Drug created on December 03, 2015 09:51 / Updated on November 02, 2019 04:43