Roger Pertwee

New potential therapeutic applications for certain phytocannabinoids revealed by pharmacological discoveries Roger Pertwee

UNIVERSITY OF ABERDEEN Cannabis - a unique source of “phytocannabinoids” (at least 112) -- plus plus atat leastleast 441441 otherother compoundscompounds

 Tetrahydrocannabinol-type  Cannabidiol-type  Cannabigerol-type  Cannabichromene-type  Cannabicyclol-type  Cannabielsoin-type  Cannabitriol-type  Miscellaneous-type  Cannabinol-type  Cannabinodiol-type air-oxidation artifacts? ElSohly, M.A. & Slade, D. (2005) Life Sci 78: 539-548 ElSohly, M.A. & Gul, W. (2014) Handbook of Cannabis, pp. 3-22 9-THC acts through cannabinoid receptors

 Discovery of CB1 & CB2 cannabinoid receptors (cloned in 1990 & 1993)

Human CB1 Receptor Human CB2 Receptor Extracellular N-terminal GPCR GPCR Extracellular N-terminal expressed expressed by neurons by immune etc cells etc

Intracellular Intracellular C-terminal C-terminal

CB1/CB2 homology = ca 44% (35% to 82% within TM domains) Δ9-THC is licensed for clinical use

THC Sativex Country USA Can, EU etc Anti-emetic Yes No Appetite stimulant Yes No Multiple sclerosis & cancer pain No Yes First licensed 1986 2005

 9-THC = dronabinol = Marinol® = synthetic (2.5, 5 or 10 mg capsules by mouth)  Sativex® = cannabis extract: mainly 9-THC & cannabidiol (oromucosal spray) Pertwee (2010) 9-THC also has non-CB /CB targets Pertwee & Curr Med Chem 1 2 Cascio (2014) 17: 1360-1381 Handbook of CB & CB GPR55 1 2 PPARγ Cannabis receptors (+) pp. 115-136 receptors (+) receptors (+) GPR18 Ligand-gated receptors (+) ion channels  glycine α1, α1 β1 (↑) Just  5-HT3A (-) Neuronal some actions uptake of of THC Cation channels  NE (+) <1 µM TRPA1 & TRPV2 (+)  DA (±) 1 to 10 µM TRPM8 (-)  5-HT(-)

Phospholipases Cellular Voltage-gated ion (+) uptake of channels & other adenosine GPCRs, TRP cation (-) channels, enzymes & Lysophosphatidylcholine cellular uptake acyl transferase activity (-) processes Pertwee (2010) 9-THC also has non-CB /CB targets Pertwee & Curr Med Chem 1 2 Cascio (2014) 17: 1360-1381 Handbook of CB & CB GPR55 1 2 PPARγ Cannabis receptors (+) pp. 115-136 receptors (+) receptors (+) GPR18 Ligand-gated receptors (+) ion channels  glycine α1, α1 β1 (↑) Just  5-HT3A (-) Neuronal some actions uptake of THC hasof THC a unique Cation channels  NE (+) pharmacological<1 µM TRPA1 & TRPV2 (+)  DA (±) “fingerprint”1 to 10 µM TRPM8 (-)  5-HT(-)

Edited by Roger Pertwee

• Includes scientific information about cannabis valuable to academic and industrial researchers

• Contains wide-ranging information about cannabis providing policymakers, government advisers, politicians, lawyers, journalists, students and parents with important relevant information about cannabis

• Each chapter is written by a group of one or more authors recognized internationally as an established expert

978-0-19-966268-5 | Hardback http://ukcatalogue.oup.com/product/9780199662685.do August 2014 | £85.00 Cannabis - a unique source of “phytocannabinoids” (at least 112) -- plus plus atat leastleast 441441 otherother compoundscompounds

 Four phytocannabinoids  tetrahydrocannabivarin (THCV) Tetrahydro- cannabivarin  cannabigerol (CBG) OH  cannabidiol (CBD)

 cannabidiolic acid (CBDA) ∆9-THCV

 Just some of their many O pharmacological targets

 the 5-HT1A receptor

 the α2 adrenoreceptor

 the CB1 and the CB2 receptor  etc etc etc  Possible new therapeutic benefits of exploiting pharmacological actions of THCV, CBG, CBD or CBDA The Pharmacology and Therapeutic Potential of Phytocannabinoids

 Four phytocannabinoids THCV:  tetrahydrocannabivarin (THCV) Potential therapeutic applications:  cannabigerol (CBG) 5-HT1A receptor-mediated – e.g.  Opioid dependence  cannabidiol (CBD)  Positive and negative symptoms  cannabidiolic acid (CBDA) of schizophrenia

 Just some of their many THCV: pharmacological targets Potential therapeutic applications: CB antagonism + CB partial agonism  the 5-HT1A receptor 1 2  Dependence/relapse: e.g. nicotine, alcohol  the α2 adrenoreceptor  Neurodegenerative disorders  the CB1 and the CB2 receptor e.g. Parkinson’s disease  etc etc etc  Systemic sclerosis  Alcohol-induced liver injury  Possible new therapeutic benefits of  Liver damage from ischaemia & reperfusion exploiting pharmacological actions  Diabetic nephropathy  Obesity of THCV, CBG, CBD or CBDA  Stroke  Retinitis pigmentosa The Pharmacology and Therapeutic Potential of Phytocannabinoids

 Four phytocannabinoids  tetrahydrocannabivarin (THCV)  cannabigerol (CBG)  cannabidiol (CBD)  cannabidiolic acid (CBDA) OHOH CannabigerolCannabigerol  Just some of their many pharmacological targets HOHO CBG  the 5-HT1A receptor

 the α2 adrenoreceptor

 Four phytocannabinoids CBG:  tetrahydrocannabivarin (THCV) Potential therapeutic applications: α2-adrenoceptor-mediated  cannabigerol (CBG)  Acute & inflammatory pain  cannabidiol (CBD)  Migraine; headaches  Cannabis & opioid dependence  cannabidiolic acid (CBDA)  Alcohol & nicotine dependence  Anxiety & panic disorders  Just some of their many  Post-traumatic stress disorder pharmacological targets  Attention-deficit hyperactivity disorder  the 5-HT receptor  Tourette syndrome (vs tics) 1A  Insomnia; sleep hyperhidrosis  the α2 adrenoreceptor  Menopausal hot flushes  Hypertension  the CB1 and the CB2 receptor

 etc etc etc 5-HT1A receptor-mediated ?  Positive and negative symptoms  Possible new therapeutic benefits of of schizophrenia exploiting pharmacological actions  Depression of THCV, CBG, CBD or CBDA  Neuropathic pain The Pharmacology and Therapeutic Potential of Phytocannabinoids

 Four phytocannabinoids  tetrahydrocannabivarin (THCV) OH  cannabigerol (CBG)  cannabidiol (CBD)  cannabidiolic acid (CBDA) CBD HOHO  Just some of their many pharmacological targets Heat

 the 5-HT1A receptor

 the α2 adrenoreceptor

 the CB1 and the CB2 receptor OH

 etc etc etc COOH  Possible new therapeutic benefits of exploiting pharmacological actions CBDA of THCV, CBG, CBD or CBDA HOHO The Pharmacology and Therapeutic Potential of Phytocannabinoids

 Four phytocannabinoids  tetrahydrocannabivarin (THCV) CBD and CBDA:  cannabigerol (CBG) Potential therapeutic applications: 5-HT1A receptor-mediated  cannabidiol (CBD)  Opioid dependence  cannabidiolic acid (CBDA)  Depression  Anxiety disorders  Just some of their many  Cognitive disorders pharmacological targets  Neuropathic pain  Nausea and vomiting  the 5-HT1A receptor  Negative symptoms of schizophrenia  Extrapyramidal syndrome  the α2 adrenoreceptor  Symptoms of Parkinson’s disease  the CB and the CB receptor 1 2  L-DOPA-induced dyskinesia  etc etc etc  Cerebral infarction/stroke  Possible new therapeutic benefits of exploiting pharmacological actions of THCV, CBG, CBD or CBDA Some pharmacological actions and potential therapeutic applications of certain phytocannabinoids: great expectations  Four phytocannabinoids  tetrahydrocannabivarin (THCV)  cannabigerol (CBG)  cannabidiol (CBD)  cannabidiolic acid (CBDA)

 Four pharmacological targets in vitro & in vivo

 the CB1 and the CB2 receptor THCV (↓CB1 plus ↑CB2)

 the α2 adrenoreceptor CBG (↑)

 the 5-HT1A receptor CBD (↑) & CBDA (↑) THCV (↑) & CBG (↓)

 Possible therapeutic benefits of targeting one or more of these receptors with THCV, CBG, CBD or CBDA Some pharmacological actions and potential therapeutic applications of certain phytocannabinoids: great expectations  Four phytocannabinoids “fighto” cannabinoids  tetrahydrocannabivarin (THCV)  cannabigerol (CBG)  cannabidiol (CBD)  cannabidiolic acid (CBDA)

 Four pharmacological targets in vitro & in vivo

 the CB1 and the CB2 receptor THCV (↓CB1 plus ↑CB2)

 the α2 adrenoreceptor CBG (↑)

 the 5-HT1A receptor CBD (↑) & CBDA (↑) THCV (↑) & CBG (↓)

 Four phytocannabinoids “fighto” cannabinoids (3) perform structure-activity studies with synthetic analogues of these  tetrahydrocannabivarin (THCV) phytocannabinoids to optimize one  cannabigerol (CBG) or more of their many potential (4) Seek out other therapeutic effects  cannabidiol (CBD) phytocannabinoid  cannabidiolic acid (CBDA) actions

 Four pharmacological targets in vitro & in vivo

 the CB1 and the CB2 receptor THCV (↓CB1 plus ↑CB2)

 the α2 adrenoreceptor CBG (↑)

 the 5-HT1A receptor CBD (↑) & CBDA (↑) THCV (↑) & CBG (↓)

 Possible therapeutic benefits of numerous targeting one or more of these receptors with THCV, CBG, CBD or CBDA

(1) identify best  CBD Some (2) explore clinical advantages of therapeutic  CBDA possible “adjunctive strategies”…e.g. application(s) for:  CBG future low-dose CBG (α2-agonism) plus  THCV directions – clinical data low-doseTHC (CB1 agonism) needed for pain relief Acknowledgements

Aberdeen Italy Canada Lesley Stevenson Barbara Costa Linda Parker Maria Grazia Cascio Vincenzo Di Marzo Pietro Marini Mauro Maccarrone USA Mirela Delibegovic Sabatino Maione Eliot Gardner Fiona Murray Daniela Parolaro Aron Lichtman Guy Bewick Tiziana Rubino Anu Mahadevan Matteo Zanda Pál Pacher PeterTeismann Spain Ganesh Thakur Dana Dawson Javier Fernández-Ruiz Heather Wilson Jenny Wiley Iain Brown et al. Xi Zheng-Xiong Ruth Ross Germany Israel Daniele Bolognini Sandor Bátkai Raphael Mechoulam Gemma Baillie Reem Smoum Lisa Gauson

Financial Support GW Pharmaceuticals, NIH (NIDA), NHS, BBSRC & Diabetes UK Published in October 2015

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