Identification

Name
Cannabidivarin
Accession Number
DB14050
Type
Small Molecule
Groups
Investigational
Description

Cannabidivarin, also known as cannabidivarol or CBDV, is a non-psychoactive cannabinoid found within Medical Cannabis. It is one of over 100 cannabinoids identified from the Cannabis plant that can modulate the physiological activity of cannabis, or marijuana [3]. Compared to its homolog, Cannabidiol, CBDV is shortened by two methyl (CH2) groups on its side chain. Notably, both Cannabidiol and CBDV have demonstrated anticonvulsant activity in animal and human models and are demonstrating promising clinical trial results [2, 4, 5, 6]. Other cannabinoids with some evidence of anti-epileptic activity include Tetrahydrocannabivarin (THCV) and Δ9-tetrahydrocannabinolic acid.

While the primary components of cannabis, CBD and THC, have been shown to modulate many of their physiological effects through their binding to the cannabinoid-1 (CB1R) and cannabinoid-2 (CB2R) receptors, the investigational cannabinoids with anticonvulsant action mostly use mechanisms that do not involve these two endocannabinoid receptors.

The anti-epileptic activity of CBD and CBDV is thought to be modulated by their effects on transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor, which is a member of a large family of ion channels that are involved in the onset and progression of several types of epilepsy. CBD and CBDV have been shown to dose-dependently activate and then desensitize TRPV1 as well as TRPV2 and TRPA1 channels [4, 7, 8]. Desensitization of these ion channels is a potential mechanism by which these molecules cause a reduction of neuronal hyperexcitability that contributes to epileptic activity and seizures.

CBDV has also been shown to inhibit the activity of diacylglycerol (DAG) lipase-α, the primary enzyme responsible for the synthesis of the endocannabinoid, 2-arachidonoylglycerol (2-AG) [1, 10]. The clinical implications of this are unclear however, as this interaction has not been shown to affect CBDV's anticonvulsant activity.

Cannabidivarin is being actively developed by GW Pharmaceuticals as the experimental compound GWP42006 as it has "shown the ability to treat seizures in pre-clinical models of epilepsy with significantly fewer side effects than currently approved anti-epileptic drugs" [13]. Unfortunately, as of February 2018, GW Pharmaceuticals announced that their Phase 2a placebo-controlled study of CBDV for focal seizure did not reach its primary endpoints. They will continue to study its use in epilepsy, however, and are expanding their investigations to include its potential use in Autism Spectrum Disorder, Rett syndrome and Fragile X among others [12].

In October 2017 CBDV was given orphan designation by the European Medicines Agency for use in Rett Syndrome [15] and again in February 2018 for treatment of Fragile X Syndrome [14].

Structure
Thumb
Synonyms
  • 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-propylbenzene-1,3-diol
  • cannabidivarine
  • Cannabidivarol
  • CBD-V
  • CBDV
External IDs
GWP 42006 / GWP-42006 / GWP42006
Categories
UNII
I198VBV98I
CAS number
24274-48-4
Weight
Average: 286.415
Monoisotopic: 286.193280077
Chemical Formula
C19H26O2
InChI Key
REOZWEGFPHTFEI-JKSUJKDBSA-N
InChI
InChI=1S/C19H26O2/c1-5-6-14-10-17(20)19(18(21)11-14)16-9-13(4)7-8-15(16)12(2)3/h9-11,15-16,20-21H,2,5-8H2,1,3-4H3/t15-,16+/m0/s1
IUPAC Name
2-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl]-5-propylbenzene-1,3-diol
SMILES
[H][C@]1(CCC(C)=C[C@H]1C1=C(O)C=C(CCC)C=C1O)C(C)=C

Pharmacology

Indication

Cannabidivarin does not currently have any FDA or Health Canada approved indications, however in October 2017 CBDV was given orphan designation by the European Medicines Agency for use in Rett Syndrome [15] and again in February 2018 for treatment of Fragile X Syndrome [14].

Pharmacodynamics
Not Available
Mechanism of action

The anti-epileptic activity of CBD and CBDV is thought to be modulated by their effects on transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor, which is part of a large family of ion channels that are involved in the onset and progression of several types of epilepsy. CBD and CBDV have been shown to dose-dependently activate and then desensitize TRPV1 as well as TRPV2 and TRPA1 channels [4, 7, 8]. Desensitization of these ion channels is a potential mechanism by which these molecules cause a reduction of neuronal hyperexcitability that contributes to epileptic activity and seizures.

CBDV has also been shown to inhibit the activity of diacylglycerol (DAG) lipase-α, the primary synthetic enzyme of the endocannabinoid, 2-arachidonoylglycerol (2-AG) [1, 10]. The clinical implications of this are unclear however, as this interaction has not been shown to affect CBDV's anticonvulsant activity.

TargetActionsOrganism
ATransient receptor potential cation channel subfamily V member 1
agonist
Human
ATransient receptor potential cation channel subfamily V member 2
agonist
Human
ATransient receptor potential cation channel subfamily A member 1
agonist
Human
USn1-specific diacylglycerol lipase alpha
inhibitor
Human
Absorption

Like Δ9-THC, CBDV has low water solubility and poor oral bioavailability (~6% in humans), making oral administration an unfavourable method of delivery. Despite this, CBDV has relatively rapid absorption with peak concentrations seen around 2 h after oral administration in animal pharmacokinetic studies [11].

Orally administered CBDV in mice was found to have a plasma Cmax of 0.47ug/mL and Tmax of 30 minutes, and a brain Cmax of 0.94ug/mL and Tmax of 60 minutes [11].

Volume of distribution

Due to its lipophilicity, CBDV has been shown to cross the blood brain barrier [11].

Protein binding
Not Available
Metabolism

Significant first-pass metabolism by the liver results in erratic absorption from the GI tract, low bioavailability, and unreliable pharmacokinetics [9].

Route of elimination
Not Available
Half life

Orally administered CBDV in mice was found to have a plasma elimination half life of 222 minutes, and a brain elimination half life of 204 minutes [11].

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

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Cannabidivarin.
3-isobutyl-1-methyl-7H-xanthineCannabidivarin may increase the excretion rate of 3-isobutyl-1-methyl-7H-xanthine which could result in a lower serum level and potentially a reduction in efficacy.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Cannabidivarin.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Cannabidivarin.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Cannabidivarin.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when 5-methoxy-N,N-dimethyltryptamine is combined with Cannabidivarin.
6-O-benzylguanineCannabidivarin may increase the excretion rate of 6-O-benzylguanine which could result in a lower serum level and potentially a reduction in efficacy.
7-DeazaguanineCannabidivarin may increase the excretion rate of 7-Deazaguanine which could result in a lower serum level and potentially a reduction in efficacy.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Cannabidivarin.
7,9-DimethylguanineCannabidivarin may increase the excretion rate of 7,9-Dimethylguanine which could result in a lower serum level and potentially a reduction in efficacy.
Food Interactions
Not Available

References

General References
  1. Amada N, Yamasaki Y, Williams CM, Whalley BJ: Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression. PeerJ. 2013 Nov 21;1:e214. doi: 10.7717/peerj.214. eCollection 2013. [PubMed:24282673]
  2. Hill AJ, Mercier MS, Hill TD, Glyn SE, Jones NA, Yamasaki Y, Futamura T, Duncan M, Stott CG, Stephens GJ, Williams CM, Whalley BJ: Cannabidivarin is anticonvulsant in mouse and rat. Br J Pharmacol. 2012 Dec;167(8):1629-42. doi: 10.1111/j.1476-5381.2012.02207.x. [PubMed:22970845]
  3. Sharma P, Murthy P, Bharath MM: Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iran J Psychiatry. 2012 Fall;7(4):149-56. [PubMed:23408483]
  4. Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, Russo E, Whalley BJ, Di Marzo V, Stephens GJ: Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci. 2014 Nov 19;5(11):1131-41. doi: 10.1021/cn5000524. Epub 2014 Jul 29. [PubMed:25029033]
  5. Capasso A: Do Cannabinoids Confer Neuroprotection Against Epilepsy? An Overview. Open Neurol J. 2017 Dec 18;11:61-73. doi: 10.2174/1874205X01711010061. eCollection 2017. [PubMed:29290836]
  6. Morano A, Cifelli P, Nencini P, Antonilli L, Fattouch J, Ruffolo G, Roseti C, Aronica E, Limatola C, Di Bonaventura C, Palma E, Giallonardo AT: Cannabis in epilepsy: From clinical practice to basic research focusing on the possible role of cannabidivarin. Epilepsia Open. 2016 Sep 19;1(3-4):145-151. doi: 10.1002/epi4.12015. eCollection 2016 Dec. [PubMed:29588939]
  7. 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]
  8. 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]
  9. Gaston TE, Friedman D: Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy Behav. 2017 May;70(Pt B):313-318. doi: 10.1016/j.yebeh.2016.11.016. Epub 2017 Jan 10. [PubMed:28087250]
  10. Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, Matias I, Schiano-Moriello A, Paul P, Williams EJ, Gangadharan U, Hobbs C, Di Marzo V, Doherty P: Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol. 2003 Nov 10;163(3):463-8. doi: 10.1083/jcb.200305129. [PubMed:14610053]
  11. Deiana S, Watanabe A, Yamasaki Y, Amada N, Arthur M, Fleming S, Woodcock H, Dorward P, Pigliacampo B, Close S, Platt B, Riedel G: Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Delta(9)-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacology (Berl). 2012 Feb;219(3):859-73. doi: 10.1007/s00213-011-2415-0. Epub 2011 Jul 28. [PubMed:21796370]
  12. GW Pharmaceuticals Announces Preliminary Results of Phase 2a Study for its Pipeline Compound GWP42006 [Link]
  13. GW Pharmaceuticals Commences Phase 1 Clinical Trial of GWP42006 as a Potential Treatment for Epilepsy [Link]
  14. Public summary of opinion on orphan designation: Cannabidivarin for treatment of fragile X syndrome [Link]
  15. Public summary of opinion on orphan designation: Cannabidivarin for the treatment of Rett syndrome [Link]
External Links
ChemSpider
9776426
ChEMBL
CHEMBL2387742
Wikipedia
Cannabidivarin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentEpilepsies1
2CompletedTreatmentEpilepsies / Seizures, Focal2
2Not Yet RecruitingTreatmentAutism Spectrum Conditions/Disorders1
Not AvailableActive Not RecruitingBasic ScienceAutism Spectrum Conditions/Disorders1

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.033 mg/mLALOGPS
logP5.13ALOGPS
logP5.44ChemAxon
logS-3.9ALOGPS
pKa (Strongest Acidic)9.13ChemAxon
pKa (Strongest Basic)-5.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area40.46 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity89.33 m3·mol-1ChemAxon
Polarizability34.04 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Transmembrane signaling receptor activity
Specific Function
Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular aci...
Gene Name
TRPV1
Uniprot ID
Q8NER1
Uniprot Name
Transient receptor potential cation channel subfamily V member 1
Molecular Weight
94955.33 Da
References
  1. Hill AJ, Mercier MS, Hill TD, Glyn SE, Jones NA, Yamasaki Y, Futamura T, Duncan M, Stott CG, Stephens GJ, Williams CM, Whalley BJ: Cannabidivarin is anticonvulsant in mouse and rat. Br J Pharmacol. 2012 Dec;167(8):1629-42. doi: 10.1111/j.1476-5381.2012.02207.x. [PubMed:22970845]
  2. Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, Russo E, Whalley BJ, Di Marzo V, Stephens GJ: Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci. 2014 Nov 19;5(11):1131-41. doi: 10.1021/cn5000524. Epub 2014 Jul 29. [PubMed:25029033]
  3. Capasso A: Do Cannabinoids Confer Neuroprotection Against Epilepsy? An Overview. Open Neurol J. 2017 Dec 18;11:61-73. doi: 10.2174/1874205X01711010061. eCollection 2017. [PubMed:29290836]
  4. 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]
  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]
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. Hill AJ, Mercier MS, Hill TD, Glyn SE, Jones NA, Yamasaki Y, Futamura T, Duncan M, Stott CG, Stephens GJ, Williams CM, Whalley BJ: Cannabidivarin is anticonvulsant in mouse and rat. Br J Pharmacol. 2012 Dec;167(8):1629-42. doi: 10.1111/j.1476-5381.2012.02207.x. [PubMed:22970845]
  2. Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, Russo E, Whalley BJ, Di Marzo V, Stephens GJ: Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci. 2014 Nov 19;5(11):1131-41. doi: 10.1021/cn5000524. Epub 2014 Jul 29. [PubMed:25029033]
  3. Capasso A: Do Cannabinoids Confer Neuroprotection Against Epilepsy? An Overview. Open Neurol J. 2017 Dec 18;11:61-73. doi: 10.2174/1874205X01711010061. eCollection 2017. [PubMed:29290836]
  4. 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]
  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]
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. Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, Russo E, Whalley BJ, Di Marzo V, Stephens GJ: Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci. 2014 Nov 19;5(11):1131-41. doi: 10.1021/cn5000524. Epub 2014 Jul 29. [PubMed:25029033]
  2. 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]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Not Available
Specific Function
Not Available
Gene Name
DAGLA
Uniprot ID
F5GY58
Uniprot Name
Sn1-specific diacylglycerol lipase alpha
Molecular Weight
19005.05 Da
References
  1. Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, Matias I, Schiano-Moriello A, Paul P, Williams EJ, Gangadharan U, Hobbs C, Di Marzo V, Doherty P: Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol. 2003 Nov 10;163(3):463-8. doi: 10.1083/jcb.200305129. [PubMed:14610053]
  2. Amada N, Yamasaki Y, Williams CM, Whalley BJ: Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression. PeerJ. 2013 Nov 21;1:e214. doi: 10.7717/peerj.214. eCollection 2013. [PubMed:24282673]

Drug created on June 07, 2018 09:55 / Updated on November 02, 2018 07:49