new potential therapeutic applications for certain ...€¦ · (35% to 82% within tm domains)...

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#