Cannabinoid pharmacology: the first 66 years

doi:10.1038/SJ.BJP.0706406

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Cannabinoid pharmacology: the first 66 years

Journal Article•DOI•

Cannabinoid pharmacology: the first 66 years

Roger G. Pertwee¹•Institutions (1)

University of Aberdeen¹

01 Jan 2006-British Journal of Pharmacology (Wiley/Blackwell (10.1111))-Vol. 147

TL;DR: Research into the pharmacology of individual cannabinoids that began in the 1940s is concisely reviewed and it is described how this pharmacological research led to the discovery of cannabinoid CB1 and CB2 receptors and of endogenous ligands for these receptors.

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Abstract: Research into the pharmacology of individual cannabinoids that began in the 1940s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Also described is how this pharmacological research led to the discovery of cannabinoid CB1 and CB2 receptors and of endogenous ligands for these receptors, to the development of CB1- and CB2-selective agonists and antagonists and to the realization that the endogenous cannabinoid systemhas significant roles in both health and disease, and that drugs which mimic, augment or block the actions of endogenously released cannabinoids must have important therapeutic applications. Some goals for future research are identified. British Journal of Pharmacology (2006) 147, S163–S171. doi:10.1038/sj.bjp.0706406

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Journal Article•DOI•

The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin

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Roger G. Pertwee¹•Institutions (1)

University of Aberdeen¹

01 Jan 2008-British Journal of Pharmacology

TL;DR: This review focuses on the manner with which three of these compounds, (−)‐trans‐Δ 9‐tetrahydrocannabinol (Δ9‐THC), (−]‐cannabidiol (CBD) and (−)-trans‐ Δ9‐TetrahYDrocannabivarin (Γ‐THCV), interact with cannabinoid CB1 and CB2 receptors.

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Abstract: Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (-)-trans-delta9-tetrahydrocannabinol (delta9-THC), (-)-cannabidiol (CBD) and (-)-trans-delta9-tetrahydrocannabivarin (delta9-THCV), interact with cannabinoid CB1 and CB2 receptors. Delta9-THC, the main psychotropic constituent of cannabis, is a CB1 and CB2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1- and CB2-expressing cells or tissues, the manner with which it interacts with CB2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Delta9-THCV behaves as a potent CB2 receptor partial agonist in vitro. In contrast, it antagonizes cannabinoid receptor agonists in CB1-expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Delta9-THCV also interacts with CB1 receptors when administered in vivo, behaving either as a CB1 antagonist or, at higher doses, as a CB1 receptor agonist. Brief mention is also made in this review, first of the production by delta9-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which delta9-THC, CBD and delta9-THCV interact with pharmacological targets other than CB1 or CB2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.

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1,492 citations

Cites background or methods from "Cannabinoid pharmacology: the first..."

...Among the effects that D9-THC seems to produce in vivo in healthy animals by activating neuronal CB1 receptors are several that are frequently used as measured responses in bioassays for CB1 receptor agonists (reviewed in Howlett et al., 2002; Pertwee, 2006)....
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...The structure and stereochemistry of the phytocannabinoid, CBD, were first elucidated by Raphael Mechoulam in the 1960s who then went on to devise a method for its synthesis (reviewed in Pertwee, 2006)....
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...bioassays for CB1 receptor agonists (reviewed in Howlett et al., 2002; Pertwee, 2006)....
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...Importantly, they also led on to the discovery that many of the effects produced by D9-THC and its synthetic cousins depend on the ability of these ligands to target a new family of receptors (reviewed in Howlett et al., 2002; Pertwee, 2005a, 2006)....
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...…to the discovery that the psychotropic effects of cannabis are produced mainly by ( )-trans-D9-tetrahydrocannabinol (D9THC; Figure 1), to the pharmacological characterization of this plant cannabinoid (phytocannabinoid) and to the development of synthetic cannabinoids (reviewed in Pert- wee, 2006)....
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Journal Article•DOI•

Targeting the endocannabinoid system: to enhance or reduce?

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Vincenzo Di Marzo¹•Institutions (1)

National Research Council¹

01 May 2008-Nature Reviews Drug Discovery

TL;DR: The discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases is discovered.

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Abstract: As our understanding of the endocannabinoids improves, so does the awareness of their complexity During pathological states, the levels of these mediators in tissues change, and their effects vary from those of protective endogenous compounds to those of dysregulated signals These observations led to the discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases When moving to the clinic, however, the pleiotropic nature of endocannabinoid functions will require careful judgement in the choice of patients and stage of the disorder for treatment

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744 citations

Cites background from "Cannabinoid pharmacology: the first..."

...These targets include the G-protein-coupled cannabinoid receptors and their endogenous ligands, the endocannabinoids...
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Journal Article•DOI•

Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System.

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Shenglong Zou¹, Ujendra Kumar¹•Institutions (1)

University of British Columbia¹

13 Mar 2018-International Journal of Molecular Sciences

TL;DR: It is believed that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.

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Abstract: The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.

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617 citations

Journal Article•DOI•

Synthetic cannabinoids: Epidemiology, pharmacodynamics, and clinical implications

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Marisol S. Castaneto¹, David A. Gorelick², Nathalie A. Desrosiers¹, Nathalie A. Desrosiers², Rebecca L. Hartman¹, Rebecca L. Hartman², Sandrine Pirard¹, Marilyn A. Huestis¹ - Show less +4 more•Institutions (2)

National Institute on Drug Abuse¹, University of Maryland, Baltimore²

01 Nov 2014-Drug and Alcohol Dependence

TL;DR: A comprehensive review, based on a systematic electronic literature search, of SC epidemiology and pharmacology and their clinical implications is presented, showing in vitro and animal in vivo studies show SC pharmacological effects 2-100 times more potent than THC.

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549 citations

Cites methods from "Cannabinoid pharmacology: the first..."

...SC were developed as research tools to explore the endocannabinoid system and as potential therapeutics (Pertwee, 2006)....
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Journal Article•DOI•

Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study of the Efficacy, Safety, and Tolerability of THC:CBD Extract and THC Extract in Patients with Intractable Cancer-Related Pain

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Jeremy R. Johnson, Mary Burnell-Nugent, Dominique Lossignol, Elena Doina E.D. Ganae-Motan, Richard R. Potts, Marie Fallon¹ - Show less +2 more•Institutions (1)

Edinburgh Cancer Research Centre¹

01 Feb 2010-Journal of Pain and Symptom Management

TL;DR: It is shown that THC:CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids.

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463 citations

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References

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Journal Article•DOI•

Isolation and structure of a brain constituent that binds to the cannabinoid receptor

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William A. Devane¹, Lumir Hanus¹, Aviva Breuer¹, Roger G. Pertwee², Lesley A. Stevenson², Graeme Griffin², Dan Gibson¹, Asher Mandelbaum³, A. Etinger³, Raphael Mechoulam¹ - Show less +6 more•Institutions (3)

Hebrew University of Jerusalem¹, University of Aberdeen², Technion – Israel Institute of Technology³

18 Dec 1992-Science

TL;DR: In this article, an arachidonylethanthanolamide (anandamide) was identified in a screen for endogenous ligands for the cannabinoid receptor and its structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and confirmed by synthesis.

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Abstract: Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.

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5,283 citations

"Cannabinoid pharmacology: the first..." refers background in this paper

...The structures and stereochemistry of CBD and D9-THC, each of which occurs naturally as its ( )-enantiomer, were elucidated in Raphael Mechoulam’s laboratory: in 1963 for CBD and in 1964 for D9-THC, when it was first isolated from cannabis....
[...]
...…whether this endogenous ligand would activate CB1 receptors, a few micrograms were sent to Aberdeen where it was found that this test material did indeed share the ability of CB1 receptor agonists to inhibit electrically evoked contractions of the mouse isolated vas deferens (Devane et al., 1992)....
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...One likely candidate was isolated from pig brain by Bill Devane, who was now working in Jerusalem with Raphael Mechoulam (Devane et al., 1992)....
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Journal Article•DOI•

International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors

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Allyn C. Howlett¹, Francis Barth, Tom I. Bonner, Guy A. Cabral, Pierre Casellas, William A. Devane, Christian C. Felder, Miles Herkenham, Ken Mackie, Billy R. Martin, Raphael Mechoulam, Roger G. Pertwee - Show less +8 more•Institutions (1)

North Carolina Central University¹

01 Jun 2002-Pharmacological Reviews

TL;DR: It is considered premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification, because pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging and other kinds of supporting evidence are still lacking.

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Abstract: Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.

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2,619 citations

"Cannabinoid pharmacology: the first..." refers background or result in this paper

...For the cannabinoids, two bioassays that proved to be successful measured ‘static ataxia’ in dogs and changes such as sedation, ptosis and body sag in monkeys (reviewed in Howlett et al., 2002)....
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...Since the discovery of CB1 and CB2 receptors, a great deal has become known about how these receptors signal and about their roles (reviewed in Howlett et al., 2002; Howlett, 2005; Pertwee, 2005b)....
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...Although often regarded as peripheral receptors, CB2 receptors have been detected in the central nervous system, for example, on microglial cells (reviewed in Howlett et al., 2002; Pertwee, 2005b)....
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...…structure, secondly, that cannabinoids with chiral British Journal of Pharmacology vol 147 (S1) centres exhibit stereoselectivity, and thirdly, that the potency of D9-THC matches that of agonists for at least some established classes of receptor (reviewed in Howlett et al., 2002; Pertwee, 2005b)....
[...]
...…classes of psychotropic cannabinoids made their appearance, for example, the aminoalkylindole R-(þ )-WIN55212, endogenous eicosanoids such as anandamide and 2-arachidonoyl glycerol (see above) and, more recently, the Bayer compound, BAY 38-7271 (reviewed in Howlett et al., 2002; Pertwee, 2005b)....
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Journal Article•DOI•

SR141716A, a potent and selective antagonist of the brain cannabinoid receptor

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Murielle Rinaldi-Carmona, Francis Barth, Michel Heaulme, David Shire, Bernard Calandra, Christian Congy, Serge Martinez, Jeanne Maruani, Gervais Neliat, Daniel Caput, P. Ferrara, Philippe Soubrie, J. C. Breliere, Gérard Le Fur - Show less +10 more

22 Aug 1994-FEBS Letters

TL;DR: SR141716A is the first selective and orally active antagonist of the brain cannabinoid receptor and should prove to be a powerful tool for investigating the in vivo functions of the anandamide/cannabinoid system.

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1,764 citations

"Cannabinoid pharmacology: the first..." refers background in this paper

...…is active in other established bioassays for cannabinoid receptor agonists (reviewed in Pertwee, 1997; 1999) and, once the first CB1-selective antagonist, SR141716A, had been developed (see below), that anandamide is susceptible to antagonism by this ligand (Rinaldi-Carmona et al., 1994)....
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Journal Article•DOI•

Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study

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Luc Van Gaal, Aila Rissanen¹, André Scheen², Olivier Ziegler, Stephan Rössner - Show less +1 more•Institutions (2)

Helsinki University Central Hospital¹, University of Liège²

16 Apr 2005-The Lancet

TL;DR: CB1 blockade with rimonabant 20 mg, combined with a hypocaloric diet over 1 year, promoted significant decrease of bodyweight and waist circumference, and improvement in cardiovascular risk factors.

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1,495 citations

"Cannabinoid pharmacology: the first..." refers background in this paper

...Indeed, SR141716A (rimonabant) will most likely soon be licensed for use as an antiobesity agent (Van Gaal et al., 2005)....
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Journal Article•DOI•

Pharmacology of cannabinoid cb1 and cb2 receptors

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Roger G. Pertwee

01 Jan 1997-Pharmacology & Therapeutics

TL;DR: This review focuses on the classification, binding properties, effector systems and distribution of cannabinoid receptors, and describes the various cannabinoid receptor agonists and antagonists now available and considers the main in vivo and in vitro bioassay methods that are generally used.

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1,456 citations

"Cannabinoid pharmacology: the first..." refers background in this paper

...It was subsequently confirmed that anandamide is active in other established bioassays for cannabinoid receptor agonists (reviewed in Pertwee, 1997; 1999) and, once the first CB1-selective antagonist, SR141716A, had been developed (see below), that anandamide is susceptible to antagonism by this…...
[...]
...The discovery of cannabinoid receptors prompted the development of a number of in vitro bioassays that could be used to monitor the activation or blockade of these receptors (reviewed in Pertwee, 1997, 2005b; Howlett et al., 2002)....
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...However, the mouse isolated vas deferens was not used for this purpose until the 1990s, initially in the U.S.A., and here in Aberdeen (reviewed in Pertwee, 1997) where the discovery that this tissue provides a sensitive and quantitative bioassay for CB1 receptor ligands arose from a collaboration…...
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...…by demonstrating that tissues rendered tolerant to established CB1 receptor agonists but not to noncannabinoid inhibitors of electrically evoked contractions such as clonidine or opioid receptor agonists (reviewed in Pertwee, 1997) also exhibit tolerance to anandamide (Pertwee et al., 1993)....
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...CB1 receptors are found predominantly but not exclusively at central and peripheral nerve terminals where they mediate inhibition of transmitter release (reviewed in Pertwee, 1997; Howlett et al., 2002)....
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