Tetrahydrocannabivarin

Identification

Name
Tetrahydrocannabivarin
Accession Number
DB11755
Type
Small Molecule
Groups
Investigational
Description

Tetrahydrocannabivarin (THCV) is a propyl analogue of tetrahydrocannabinol (Δ9-THC), one of the primary pharmacological components of Medical Cannabis. Δ9-THC is currently available in several synthetic forms, including Dronabinol, while purified or isolated THCV is not approved for any medical uses and is not available as any marketed products. As a major phytocannabinoid, however, THCV is accessible within Medical Cannabis along with other identified cannabinoids including Cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabivarin (CBV), and Cannabidivarin (CBDV).

THCV is one of four cannabinoids with identified potential as anticonvulsant agents, which also includehttps://www.drugbank.ca/lims/drugs/DB11755/edit#s Δ9-tetrahydrocannabinolic acid, Cannabidiol (CBD), and Cannabidivarin (CBDV) [11].

Although THCV possesses an almost identical structure to Δ9-THC (varying only by the length of its lipophilic alkyl chain), it has different molecular targets and pharmacological profile [1]. Compared to THC which demonstrates its effects through weak partial agonist activity of both endocannabinoid receptors Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R), THCV acts as a CB1 antagonist and a partial agonist of CB2 [2]. Further evidence has also shown that THCV acts as an agonist of GPR55 and l-α-lysophosphatidylinositol (LPI) [3]. Beyond the endocannabinoid system, THCV has also been reported to activate 5HT1A receptors to produce an antipsychotic effect that has therapeutic potential for ameliorating some of the negative, cognitive and positive symptoms of schizophrenia [4]. Furthermore, THCV interacts with different transient receptor potential (TRP) channels including TRPV2, which may contribute to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts [5]. It has also shown antiepileptiform and anticonvulsant properties, that suggest possible therapeutic application in the treatment of pathophysiologic hyperexcitability states such as untreatable epilepsy [10].

Cannabinoid receptors are utilized endogenously by the body through the endocannabinoid system, which includes a group of lipid proteins, enzymes, and receptors that are involved in many physiological processes. Through its modulation of neurotransmitter release, the endocannabinoid system regulates cognition, pain sensation, appetite, memory, sleep, immune function, and mood among many others. These effects are largely mediated through two members of the G-protein coupled receptor family, cannabinoid receptors 1 and 2 (CB1 and CB2)[6]. CB1 receptors are found in both the central and peripheral nervous systems, with the majority of receptors localized to the hippocampus and amygdala of the brain. Physiological effects of using cannabis make sense in the context of its receptor activity as the hippocampus and amygdala are primarily involved with regulation of memory, fear, and emotion. In contrast, CB2 receptors are mainly found peripherally in immune cells, lymphoid tissue, and peripheral nerve terminals [7].

Reliably studying the effects of Cannabis (and of THCV) is complicated by the numerous other compounds that Cannabis contains such as terpenes, flavonoids, phenols, amino acids, and fatty acids among many others that have the potential to modulate the plant's pharmacological effect [8, 9].

Structure
Thumb
Synonyms
  • THCV
External IDs
GWP-42004 / GWP42004 / O-4394
Categories
UNII
I5YE3I47D8
CAS number
31262-37-0
Weight
Average: 286.415
Monoisotopic: 286.193280077
Chemical Formula
C19H26O2
InChI Key
ZROLHBHDLIHEMS-HUUCEWRRSA-N
InChI
InChI=1S/C19H26O2/c1-5-6-13-10-16(20)18-14-9-12(2)7-8-15(14)19(3,4)21-17(18)11-13/h9-11,14-15,20H,5-8H2,1-4H3/t14-,15-/m1/s1
IUPAC Name
(6aR,10aR)-6,6,9-trimethyl-3-propyl-6H,6aH,7H,8H,10aH-benzo[c]isochromen-1-ol
SMILES
CCCC1=CC(O)=C2[C@@H]3C=C(C)CC[C@H]3C(C)(C)OC2=C1

Pharmacology

Indication

THCV does not currently have any FDA, Health Canada, or EMA approved indications.

Pharmacodynamics

Compared to THC which demonstrates its effects through weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors, THCV acts as a CB1 antagonist and a partial agonist of CB2 [2]. Further evidence has also shown that THCV acts as an agonist of GPR55 and l-α-lysophosphatidylinositol (LPI) [3]. Beyond the endocannabinoid system, THCV has also been reported to activate 5HT1A receptors to produce an antipsychotic effect that has therapeutic potential for ameliorating some of the negative, cognitive and positive symptoms of schizophrenia [4]. Furthermore, THCV interacts with different transient receptor potential (TRP) channels including TRPV1, which may contribute to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts [5].

Mechanism of action
TargetActionsOrganism
ACannabinoid receptor 1
antagonist
Human
UCannabinoid receptor 2
partial agonist
Human
AG-protein coupled receptor 55
partial agonist
Human
A5-hydroxytryptamine receptor 1A
agonist
Human
ATransient receptor potential cation channel subfamily V member 2
agonist
Human
ATransient receptor potential cation channel subfamily M member 8
antagonist
Human
ATransient receptor potential cation channel subfamily A member 1
agonist
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
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of adverse effects can be increased when Tetrahydrocannabivarin is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of adverse effects can be increased when Tetrahydrocannabivarin is combined with (S)-Warfarin.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Tetrahydrocannabivarin is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Tetrahydrocannabivarin.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Tetrahydrocannabivarin.
4-hydroxycoumarinThe risk or severity of adverse effects can be increased when Tetrahydrocannabivarin is combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Tetrahydrocannabivarin.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Tetrahydrocannabivarin is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Tetrahydrocannabivarin.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of adverse effects can be increased when 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline is combined with Tetrahydrocannabivarin.
Food Interactions
Not Available

References

General References
  1. Morales P, Hurst DP, Reggio PH: Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131. doi: 10.1007/978-3-319-45541-9_4. [PubMed:28120232]
  2. Pertwee RG: The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008 Jan;153(2):199-215. doi: 10.1038/sj.bjp.0707442. Epub 2007 Sep 10. [PubMed:17828291]
  3. Anavi-Goffer S, Baillie G, Irving AJ, Gertsch J, Greig IR, Pertwee RG, Ross RA: Modulation of L-alpha-lysophosphatidylinositol/GPR55 mitogen-activated protein kinase (MAPK) signaling by cannabinoids. J Biol Chem. 2012 Jan 2;287(1):91-104. doi: 10.1074/jbc.M111.296020. Epub 2011 Oct 25. [PubMed:22027819]
  4. Cascio MG, Zamberletti E, Marini P, Parolaro D, Pertwee RG: The phytocannabinoid, Delta(9)-tetrahydrocannabivarin, can act through 5-HT(1)A receptors to produce antipsychotic effects. Br J Pharmacol. 2015 Mar;172(5):1305-18. doi: 10.1111/bph.13000. [PubMed:25363799]
  5. De Petrocellis L, Ligresti A, Moriello AS, Allara M, Bisogno T, Petrosino S, Stott CG, Di Marzo V: Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011 Aug;163(7):1479-94. doi: 10.1111/j.1476-5381.2010.01166.x. [PubMed:21175579]
  6. Zou S, Kumar U: Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci. 2018 Mar 13;19(3). pii: ijms19030833. doi: 10.3390/ijms19030833. [PubMed:29533978]
  7. Kaur R, Ambwani SR, Singh S: Endocannabinoid System: A Multi-Facet Therapeutic Target. Curr Clin Pharmacol. 2016;11(2):110-7. [PubMed:27086601]
  8. Pollastro F, Minassi A, Fresu LG: Cannabis Phenolics and their Bioactivities. Curr Med Chem. 2018;25(10):1160-1185. doi: 10.2174/0929867324666170810164636. [PubMed:28799497]
  9. Baron EP: Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It's Been .... Headache. 2015 Jun;55(6):885-916. doi: 10.1111/head.12570. Epub 2015 May 25. [PubMed:26015168]
  10. Hill AJ, Weston SE, Jones NA, Smith I, Bevan SA, Williamson EM, Stephens GJ, Williams CM, Whalley BJ: Delta(9)-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats. Epilepsia. 2010 Aug;51(8):1522-32. doi: 10.1111/j.1528-1167.2010.02523.x. Epub 2010 Feb 26. [PubMed:20196794]
  11. Ruzic Zecevic D, Folic M, Tantoush Z, Radovanovic M, Babic G, Jankovic SM: Investigational cannabinoids in seizure disorders, what have we learned thus far? Expert Opin Investig Drugs. 2018 Jun 6:1-7. doi: 10.1080/13543784.2018.1482275. [PubMed:29842819]
External Links
PubChem Compound
93147
PubChem Substance
347828110
ChemSpider
84092
ChEMBL
CHEMBL2387541
Wikipedia
Tetrahydrocannabivarin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentDyslipidemias / Type 2 Diabetes Mellitus1
2CompletedTreatmentType 2 Diabetes Mellitus1

Pharmacoeconomics

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

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0089 mg/mLALOGPS
logP6.08ALOGPS
logP5.06ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)9.34ChemAxon
pKa (Strongest Basic)-4.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area29.46 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity87.53 m3·mol-1ChemAxon
Polarizability34.7 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
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 2,2-dimethyl-1-benzopyrans. These are organic compounds containing a 1-benzopyran moiety that carries two methyl groups at the 2-position.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzopyrans
Sub Class
1-benzopyrans
Direct Parent
2,2-dimethyl-1-benzopyrans
Alternative Parents
Alkyl aryl ethers / 1-hydroxy-4-unsubstituted benzenoids / 1-hydroxy-2-unsubstituted benzenoids / Oxacyclic compounds / Hydrocarbon derivatives
Substituents
2,2-dimethyl-1-benzopyran / 1-hydroxy-4-unsubstituted benzenoid / 1-hydroxy-2-unsubstituted benzenoid / Alkyl aryl ether / Benzenoid / Oxacycle / Ether / Organic oxygen compound / Hydrocarbon derivative / Organooxygen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Drug binding
Specific Function
Involved in cannabinoid-induced CNS effects. Acts by inhibiting adenylate cyclase. Could be a receptor for anandamide. Inhibits L-type Ca(2+) channel current. Isoform 2 and isoform 3 have altered l...
Gene Name
CNR1
Uniprot ID
P21554
Uniprot Name
Cannabinoid receptor 1
Molecular Weight
52857.365 Da
References
  1. Morales P, Hurst DP, Reggio PH: Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131. doi: 10.1007/978-3-319-45541-9_4. [PubMed:28120232]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Partial agonist
General Function
Cannabinoid receptor activity
Specific Function
Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and b...
Gene Name
CNR2
Uniprot ID
P34972
Uniprot Name
Cannabinoid receptor 2
Molecular Weight
39680.275 Da
References
  1. Morales P, Hurst DP, Reggio PH: Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131. doi: 10.1007/978-3-319-45541-9_4. [PubMed:28120232]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Partial agonist
General Function
G-protein coupled receptor activity
Specific Function
May be involved in hyperalgesia associated with inflammatory and neuropathic pain (By similarity). Receptor for L-alpha-lysophosphatidylinositol (LPI). LPI induces Ca(2+) release from intracellular...
Gene Name
GPR55
Uniprot ID
Q9Y2T6
Uniprot Name
G-protein coupled receptor 55
Molecular Weight
36637.12 Da
References
  1. Morales P, Hurst DP, Reggio PH: Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131. doi: 10.1007/978-3-319-45541-9_4. [PubMed:28120232]
  2. Anavi-Goffer S, Baillie G, Irving AJ, Gertsch J, Greig IR, Pertwee RG, Ross RA: Modulation of L-alpha-lysophosphatidylinositol/GPR55 mitogen-activated protein kinase (MAPK) signaling by cannabinoids. J Biol Chem. 2012 Jan 2;287(1):91-104. doi: 10.1074/jbc.M111.296020. Epub 2011 Oct 25. [PubMed:22027819]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers...
Gene Name
HTR1A
Uniprot ID
P08908
Uniprot Name
5-hydroxytryptamine receptor 1A
Molecular Weight
46106.335 Da
References
  1. Morales P, Hurst DP, Reggio PH: Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131. doi: 10.1007/978-3-319-45541-9_4. [PubMed:28120232]
  2. Cascio MG, Zamberletti E, Marini P, Parolaro D, Pertwee RG: The phytocannabinoid, Delta(9)-tetrahydrocannabivarin, can act through 5-HT(1)A receptors to produce antipsychotic effects. Br J Pharmacol. 2015 Mar;172(5):1305-18. doi: 10.1111/bph.13000. [PubMed:25363799]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Calcium-permeable, non-selective cation channel with an outward rectification. Seems to be regulated, at least in part, by IGF-I, PDGF and neuropeptide head activator. May transduce physical stimuli in mast cells. Activated by temperatures higher than 52 degrees Celsius; is not activated by vanilloids and acidic pH.
Specific Function
Calcium channel activity
Gene Name
TRPV2
Uniprot ID
Q9Y5S1
Uniprot Name
Transient receptor potential cation channel subfamily V member 2
Molecular Weight
85980.335 Da
References
  1. Morales P, Hurst DP, Reggio PH: Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131. doi: 10.1007/978-3-319-45541-9_4. [PubMed:28120232]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Calcium channel activity
Specific Function
Receptor-activated non-selective cation channel involved in detection of sensations such as coolness, by being activated by cold temperature below 25 degrees Celsius. Activated by icilin, eucalypto...
Gene Name
TRPM8
Uniprot ID
Q7Z2W7
Uniprot Name
Transient receptor potential cation channel subfamily M member 8
Molecular Weight
127684.035 Da
References
  1. Morales P, Hurst DP, Reggio PH: Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131. doi: 10.1007/978-3-319-45541-9_4. [PubMed:28120232]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Temperature-gated cation channel activity
Specific Function
Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in t...
Gene Name
TRPA1
Uniprot ID
O75762
Uniprot Name
Transient receptor potential cation channel subfamily A member 1
Molecular Weight
127499.88 Da
References
  1. Morales P, Hurst DP, Reggio PH: Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131. doi: 10.1007/978-3-319-45541-9_4. [PubMed:28120232]

Drug created on October 20, 2016 14:45 / Updated on November 02, 2018 07:15