1.02020-03-19 00:34:54 UTC2020-11-18 16:35:09 UTCCDB000006CannabigerovarinCannabidivarin (CBDV) is a non-psychoactive cannabinoid found within medical Cannabis. It is one of over 100 cannabinoids identified from the Cannabis plants that can modulate the physiological activity of cannabis, or marijuana (PubMed ID 23408483). CBDV is the C3 analogue of cannabidiol (CBD). Notably, both cannabidiol and CBDV have demonstrated anticonvulsant activity in animal and human models and are demonstrating promising clinical trial results (PMID: 22970845; PMID: 25029033; PMID: 29290836; PMID: 29588939). 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 (PMID 25029033; PMID: 29842819; PMID: 21175579). 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) (PMID: 24282673; PMID: 14610053). 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". 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. In October 2017 CBDV was given orphan designation by the European Medicines Agency for use in Rett Syndrome and again in February 2018 for treatment of Fragile X Syndrome. C19H28O2288.43288.20892-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-5-propylbenzene-1,3-diol2-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-5-propylbenzene-1,3-diol55824-11-8CCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1InChI=1S/C19H28O2/c1-5-7-16-12-18(20)17(19(21)13-16)11-10-15(4)9-6-8-14(2)3/h8,10,12-13,20-21H,5-7,9,11H2,1-4H3/b15-10+YJYIDZLGVYOPGU-XNTDXEJSSA-N belongs to the class of organic compounds known as aromatic monoterpenoids. These are monoterpenoids containing at least one aromatic ring.Aromatic monoterpenoidsOrganic compoundsLipids and lipid-like moleculesPrenol lipidsMonoterpenoidsAromatic homomonocyclic compounds1-hydroxy-2-unsubstituted benzenoids1-hydroxy-4-unsubstituted benzenoidsHydrocarbon derivativesMonocyclic monoterpenoidsOrganooxygen compoundsPhenylpropanesResorcinols1-hydroxy-2-unsubstituted benzenoid1-hydroxy-4-unsubstituted benzenoidAromatic homomonocyclic compoundAromatic monoterpenoidBenzenoidHydrocarbon derivativeMonocyclic benzene moietyMonocyclic monoterpenoidOrganic oxygen compoundOrganooxygen compoundPhenolPhenylpropaneResorcinollogp5.91logs-4.57logp6.16pka_strongest_acidic9.16pka_strongest_basic-5.7iupac2-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-5-propylbenzene-1,3-diolaverage_mass288.43mono_mass288.2089smilesCCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1formulaC19H28O2inchiInChI=1S/C19H28O2/c1-5-7-16-12-18(20)17(19(21)13-16)11-10-15(4)9-6-8-14(2)3/h8,10,12-13,20-21H,5-7,9,11H2,1-4H3/b15-10+inchikeyYJYIDZLGVYOPGU-XNTDXEJSSA-Npolar_surface_area40.46refractivity92.31polarizability35.2rotatable_bond_count7acceptor_count2donor_count2physiological_charge0formal_charge0number_of_rings1bioavailability1rule_of_fiveYesghose_filterYesveber_ruleYesmddr_like_ruleYes59444407Hill 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.22970845Iannotti 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 29.25029033Capasso A: Do Cannabinoids Confer Neuroprotection Against Epilepsy? An Overview. Open Neurol J. 2017 Dec 18;11:61-73. doi: 10.2174/1874205X01711010061. eCollection 2017.29290836Morano 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.29588939Ruzic 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;27(6):535-541. doi: 10.1080/13543784.2018.1482275. Epub 2018 Jun 6.29842819De 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.21175579Amada 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 2013.24282673Bisogno 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.200305129.14610053