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TRANSCRIPT
New potential therapeutic applications for certain phytocannabinoids revealed
by pharmacological discoveries
Roger Pertwee
UNIVERSITYOF ABERDEEN
ElSohly, M.A. & Slade, D. (2005) Life Sci 78: 539-548ElSohly, M.A. & Gul, W. (2014) Handbook of Cannabis, pp. 3-22
air-oxidationartifacts?
Tetrahydrocannabinol-type Cannabidiol-type Cannabigerol-type Cannabichromene-type Cannabicyclol-type Cannabielsoin-type Cannabitriol-type Miscellaneous-type Cannabinol-type Cannabinodiol-type
Cannabis - a unique source of “phytocannabinoids”(at least 112) - plus at least 441 other compounds- plus at least 441 other compounds
Human CB1 Receptor Human CB2 ReceptorExtracellular N-terminal
IntracellularC-terminal
Y
ExtracellularN-terminal
IntracellularC-terminal
CB1/CB2 homology = ca 44% (35% to 82% within TM domains)
Discovery of CB1 & CB2 cannabinoid receptors (cloned in 1990 & 1993)
9-THC acts through cannabinoid receptors
GPCR GPCR
expressed by neurons
etc
expressed by immune
cells etc
Δ9-THC is licensed for clinical use
CountryAnti-emetic
Appetite stimulantMultiple sclerosis & cancer pain
First licensed
THCUSAYesYesNo1986
9-THC = dronabinol = Marinol® = synthetic(2.5, 5 or 10 mg capsules by mouth)
SativexCan, EU etcNoNoYes2005
Sativex® = cannabis extract: mainly 9-THC & cannabidiol(oromucosal spray)
9-THC also has non-CB1/CB2 targets
<1 µM1 to 10 µM
Pertwee (2010)Curr Med Chem
17: 1360-1381
Pertwee & Cascio (2014)
Handbook of Cannabis
pp. 115-136PPARγ
receptors (+)
Lysophosphatidylcholineacyl transferase activity (-)
Neuronal uptake of NE (+) DA (±) 5-HT(-)
Cellular uptake ofadenosine
(-)
GPR18receptors (+)
GPR55 receptors (+)
CB1 & CB2receptors (+)
Ligand-gated ion channels
glycine α1, α1 β1 (↑) 5-HT3A (-)
Cation channelsTRPA1 & TRPV2 (+)
TRPM8 (-)
Phospholipases(+)Voltage-gated ion
channels & other GPCRs, TRP cation
channels, enzymes & cellular uptake
processes
Just some actions
of THC
9-THC also has non-CB1/CB2 targets
Just some actions
of THC<1 µM
1 to 10 µM
Pertwee (2010)Curr Med Chem
17: 1360-1381
Pertwee & Cascio (2014)
Handbook of Cannabis
pp. 115-136
THC has a uniquepharmacological
“fingerprint”
PPARγreceptors (+)
Lysophosphatidylcholineacyl transferase activity (-)
Neuronal uptake of NE (+) DA (±) 5-HT(-)
Cellular uptake ofadenosine
(-)
GPR18receptors (+)
GPR55 receptors (+)
CB1 & CB2receptors (+)
Ligand-gated ion channels
glycine α1, α1 β1 (↑) 5-HT3A (-)
Cation channelsTRPA1 & TRPV2 (+)
TRPM8 (-)
Phospholipases(+)Voltage-gated ion
channels & other GPCRs, TRP cation
channels, enzymes & cellular uptake
processes
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 August 2014 | £85.00
Handbook of Cannabis
http://ukcatalogue.oup.com/product/9780199662685.do
ElSohly, M.A. & Slade, D. (2005) Life Sci 78: 539-548ElSohly, M.A. & Gul, W. (2014) Handbook of Cannabis, pp. 3-22
air-oxidationartifacts?
Tetrahydrocannabinol-type Cannabidiol-type Cannabigerol-type Cannabichromene-type Cannabicyclol-type Cannabielsoin-type Cannabitriol-type Miscellaneous-type Cannabinol-type Cannabinodiol-type
Cannabis - a unique source of “phytocannabinoids”(at least 112) - plus at least 441 other compounds- plus at least 441 other compounds
the CB1 and the CB2 receptor
Possible new therapeutic benefits of exploiting pharmacological actions of THCV, CBG, CBD or CBDA
cannabigerol (CBG) tetrahydrocannabivarin (THCV)
Four phytocannabinoids
the 5-HT1A receptor the α2 adrenoreceptor
Just some of their many pharmacological targets
etc etc etc
cannabidiol (CBD) cannabidiolic acid (CBDA) ∆9-THCV
O
OH
Tetrahydro-cannabivarin
The Pharmacology and Therapeutic Potential of Phytocannabinoids
THCV:Potential therapeutic applications:CB1 antagonism + CB2 partial agonism Dependence/relapse: e.g. nicotine, alcohol Neurodegenerative disorders
e.g. Parkinson’s disease Systemic sclerosis Alcohol-induced liver injury Liver damage from ischaemia & reperfusion Diabetic nephropathy Obesity Stroke Retinitis pigmentosa
THCV:Potential therapeutic applications:5-HT1A receptor-mediated – e.g. Opioid dependence Positive and negative symptoms
of schizophrenia
the CB1 and the CB2 receptor
Possible new therapeutic benefits of exploiting pharmacological actions of THCV, CBG, CBD or CBDA
cannabigerol (CBG) cannabidiol (CBD)
tetrahydrocannabivarin (THCV) Four phytocannabinoids
the 5-HT1A receptor the α2 adrenoreceptor
cannabidiolic acid (CBDA)
Just some of their many pharmacological targets
etc etc etc
The Pharmacology and Therapeutic Potential of Phytocannabinoids
Cannabigerol
HO
OH
CBG
OH
HO
Cannabigerol
the CB1 and the CB2 receptor
Possible new therapeutic benefits of exploiting pharmacological actions of THCV, CBG, CBD or CBDA
cannabigerol (CBG) cannabidiol (CBD)
tetrahydrocannabivarin (THCV) Four phytocannabinoids
the 5-HT1A receptor the α2 adrenoreceptor
cannabidiolic acid (CBDA)
Just some of their many pharmacological targets
etc etc etc
The Pharmacology and Therapeutic Potential of Phytocannabinoids
the CB1 and the CB2 receptor
Possible new therapeutic benefits of exploiting pharmacological actions of THCV, CBG, CBD or CBDA
cannabigerol (CBG) cannabidiol (CBD)
tetrahydrocannabivarin (THCV) Four phytocannabinoids
the 5-HT1A receptor the α2 adrenoreceptor
cannabidiolic acid (CBDA)
Just some of their many pharmacological targets
etc etc etc
The Pharmacology and Therapeutic Potential of Phytocannabinoids
CBG:Potential therapeutic applications:α2-adrenoceptor-mediated Acute & inflammatory pain Migraine; headaches Cannabis & opioid dependence Alcohol & nicotine dependence Anxiety & panic disorders Post-traumatic stress disorder Attention-deficit hyperactivity disorder Tourette syndrome (vs tics) Insomnia; sleep hyperhidrosis Menopausal hot flushes Hypertension
5-HT1A receptor-mediated Positive and negative symptoms
of schizophrenia Depression Neuropathic pain
?
the CB1 and the CB2 receptor
Possible new therapeutic benefits of exploiting pharmacological actions of THCV, CBG, CBD or CBDA
cannabigerol (CBG) cannabidiol (CBD)
tetrahydrocannabivarin (THCV) Four phytocannabinoids
the 5-HT1A receptor the α2 adrenoreceptor
cannabidiolic acid (CBDA)
Just some of their many pharmacological targets
etc etc etc
The Pharmacology and Therapeutic Potential of Phytocannabinoids
OH
HO CBDHO
OH
OH
HO CBDAHO
OH
COOH
Heat
the CB1 and the CB2 receptor
Possible new therapeutic benefits of exploiting pharmacological actions of THCV, CBG, CBD or CBDA
cannabigerol (CBG) tetrahydrocannabivarin (THCV)
Four phytocannabinoids
the 5-HT1A receptor the α2 adrenoreceptor
Just some of their many pharmacological targets
etc etc etc
cannabidiol (CBD) cannabidiolic acid (CBDA)
The Pharmacology and Therapeutic Potential of Phytocannabinoids
CBD and CBDA:Potential therapeutic applications:5-HT1A receptor-mediated Opioid dependence Depression Anxiety disorders Cognitive disorders Neuropathic pain Nausea and vomiting Negative symptoms of schizophrenia Extrapyramidal syndrome Symptoms of Parkinson’s disease L-DOPA-induced dyskinesia Cerebral infarction/stroke
Four pharmacological targets
the 5-HT1A receptor
Possible therapeutic benefits of targeting one or more of these receptors with THCV, CBG, CBD or CBDA
cannabigerol (CBG) cannabidiol (CBD)
tetrahydrocannabivarin (THCV) Four phytocannabinoids
the CB1 and the CB2 receptor the α2 adrenoreceptor
cannabidiolic acid (CBDA)
Some pharmacological actions and potential therapeutic applications of certain phytocannabinoids: great expectations
CBD (↑) & CBDA (↑) THCV (↑) & CBG (↓)CBG (↑)
THCV (↓CB1 plus ↑CB2)in vitro & in vivo
Four pharmacological targets
the 5-HT1A receptor
Possible therapeutic benefits of targeting one or more of these receptors with THCV, CBG, CBD or CBDA
cannabigerol (CBG) cannabidiol (CBD)
tetrahydrocannabivarin (THCV) Four phytocannabinoids
the CB1 and the CB2 receptor the α2 adrenoreceptor
cannabidiolic acid (CBDA)
Some pharmacological actions and potential therapeutic applications of certain phytocannabinoids: great expectations
CBD (↑) & CBDA (↑) THCV (↑) & CBG (↓)CBG (↑)
THCV (↓CB1 plus ↑CB2)in vitro & in vivo
“fighto” cannabinoids
Four pharmacological targets
the 5-HT1A receptor
Possible therapeutic benefits of targeting one or more of these receptors with THCV, CBG, CBD or CBDA
cannabigerol (CBG) cannabidiol (CBD)
tetrahydrocannabivarin (THCV) Four phytocannabinoids
the CB1 and the CB2 receptor the α2 adrenoreceptor
cannabidiolic acid (CBDA)
Some pharmacological actions and potential therapeutic applications of certain phytocannabinoids: great expectations
CBD (↑) & CBDA (↑) THCV (↑) & CBG (↓)CBG (↑)
THCV (↓CB1 plus ↑CB2)in vitro & in vivo
numerous
(1) identify best therapeutic application(s) for:
CBD CBDA CBG THCV
Some possible
future directions – clinical data
needed
(2) explore clinical advantages of “adjunctive strategies”…e.g. low-dose CBG (α2-agonism) plus low-doseTHC (CB1 agonism) for pain relief
(3) perform structure-activity studies with synthetic analogues of these phytocannabinoids to optimize one or more of their many potential therapeutic effects
“fighto” cannabinoids
(4) Seek out other phytocannabinoidactions
Financial SupportGW Pharmaceuticals, NIH (NIDA), NHS, BBSRC & Diabetes UK
Acknowledgements
USAEliot Gardner Aron LichtmanAnu MahadevanPál PacherGanesh ThakurJenny WileyXi Zheng-Xiong
ItalyBarbara CostaVincenzo Di MarzoMauro MaccarroneSabatino MaioneDaniela ParolaroTiziana Rubino
IsraelRaphael MechoulamReem Smoum
SpainJavier Fernández-Ruiz
CanadaLinda Parker
GermanySandor Bátkai
AberdeenLesley StevensonMaria Grazia CascioPietro MariniMirela DelibegovicFiona MurrayGuy BewickMatteo ZandaPeterTeismannDana DawsonHeather WilsonIain Brown et al.Ruth RossDaniele BologniniGemma BaillieLisa Gauson
Published in October 2015
http://www.springer.com/gb/book/9783319208244#