Cannabinoid Receptor LigandsRoger G Pertwee School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. Phone: + 44 (0)1224 555740, Fax: + 44 (0)1224 555844, E-mail: email@example.com
Roger Pertwee is currently Professor of Neuropharmacology at the University of Aberdeen and Director of Pharmacology for GW Pharmaceuticals. His research focuses on the pharmacology of cannabis and its constituents and of cannabinoid receptors and cannabis-derived, synthetic and endogenous ligands for these receptors.
The Endocannabinoid System
Two types of cannabinoid receptor have so far been identified. 1,2 These are the CB 1 receptor, cloned in 1990, 3 and the CB 2 receptor, cloned in 1993, 4 both of which are members of the superfamily of G-protein-coupled receptors. The cloning of these receptors prompted the development of mice from which cannabinoid CB 1 and/or CB 2 receptors have been genetically deleted and these transgenic animals, particularly CB 1 knockout mice, are now widely used to explore the physiological and pathological functions of cannabinoid receptors. 1,5,6 CB 1 receptors are found mainly at the terminals of central and peripheral neurons where they usually mediate inhibition of neurotransmitter release. They are also present in some non-neuronal cells, including immune cells. CB 2 receptors are located predominantly in immune cells both within and outside the central nervous system, the functions of these receptors including modulation of cytokine release and of immune cell migration. In the brain, CB 2 receptors are expressed by microglia, 7 by blood vessels, 7 and by some neurons. 8,9 However, the role of neuronal CB 2 receptors is currently unknown.
The central distribution pattern of CB 1 receptors is heterogeneous and accounts for several prominent pharmacological properties of CB 1 receptor agonists, for example their ability to impair cognition and memory and to alter the control of motor function.Thus the cerebral cortex, hippocampus, lateral caudate-putamen, substantia nigra pars reticulata, globus pallidus, entopeduncular nucleus and the molecular layer of the cerebellum are all populated with particularly high concentrations of CB 1 receptors. 1,10 In line with the analgesic properties of cannabinoid receptor agonists, CB 1 receptors are also found on pain pathways in the brain and spinal cord and at the peripheral terminals of primary sensory neurons. 11,12 Although the concentration of CB 1 receptors is considerably less in peripheral tissues than in the central nervous system, this does not mean that peripheral CB 1 receptors are unimportant. Thus in some peripheral tissues, discrete regions such as nerve terminals that form only a small part of the total tissue mass are known to be densely populated with CB 1 receptors. Peripheral tissues in which CB 1 receptors are expressed on neurons include the heart, vas deferens, urinary bladder and small DAGL α and DAGL β . 23,24 Following their synthesis and intestine. 10,13
Both CB 1 and CB 2 receptors are coupled through G i/o proteins, negatively to adenylyl cyclase and positively to mitogen-activated protein kinase. 1,14 In addition, CB 1 receptors are coupled to ion channels through G i/o proteins, positively toA-type and inwardly rectifying potassium channels and negatively to N-type and P/Q-type calcium channels. 1,13,14 CB 1 receptors can also couple to G s proteins to activate adenylyl cyclase, 15-17 the extent to which this occurs possibly being determined by the location of these receptors or by cross-talk between CB 1 receptors and co localised G-protein-coupled non-CB 1 N -oleoyl dopamine (OLDA) (Figures 2 and 3). 5 receptors. 15,16,18,19 It may also be that CB 1 receptors can exist as two distinct subpopulations, one coupled to G i/o proteins and the other to G s . 15 Details of additional signalling mechanisms that have been proposed for cannabinoid CB 1 and CB 2 receptors can be found elsewhere. 1,14
The cloning of cannabinoid receptors was followed by the discovery that mammalian tissues produce compounds that can activate these receptors.The first such endogenous cannabinoids (endocannabinoids) to be identified were N -arachidonoyl ethanolamine (anandamide) in 1992 and 2-arachidonylglycerol in 1995 (Figure 1), 20-22 both of which are synthesized on demand in response to elevations of intracellular calcium. 23 Anandamideisformedfrom N —arachidonoyl phosphatidylethanolamine in a process that is catalysed by N -acyl phosphatidylethanolamine selective phospholipase D (NAPE-PLD). The synthesis of 2-arachidonylglycerol, however, is thought to depend on the conversion of 2-arachidonate-containing phosphoinositides to diacylglycerols and on their subsequent transformation to 2-arachidonylglycerol by the action of two diacylglycerol lipase (DAGL) isozymes, release, these endocannabinoids are removed from their sites of action by cellular uptake and degraded by enzymes, 2-arachidonylglycerol mainly by monoacylglycerol lipase (MAGL) but also by fatty acid amide hydrolase (FAAH), and anandamide by FAAH and/or by palmitoylethanolamide-preferring acid amidase (PAA), cyclooxygenase-2, lipoxygenases and cytochrome P450. 5,23-25 Other ligands that may be endocannabinoids are 2-arachidonylglyceryl ether (noladin ether), O -arachidonoyl ethanolamine (virodhamine), N -dihomo- γ -linolenoyl ethanolamine, N —docosatetraenoyl ethanolamine, oleamide, N —arachidonoyl dopamine (NADA) and Endocannabinoids together with their receptors constitute what is now usually referred to as the 'endocannabinoid system'.
While it is generally accepted that endocannabinoids do pass through cell membranes, one issue that is currently very much a matter of debate is the question of whether the cellular uptake of endocannabinoids such as anandamide is mediated by a transporter. 25-27 In contrast, FAAH is now well characterised. Indeed, it has been cloned 28 and FAAH knockout mice have been developed. 29,30 NAPE/PLD, 31 MAGL, 32-34 and DAGL α and DAGL β 35 have also been cloned, and mice with a genetic deletion of NAPE/PLD generated. 36
At least some effects induced by endogenously released anandamide and 2-arachidonylglycerol appear to be enhanced through what has been termed the "entourage effect". This relies on the co-release of other endogenous fatty acid derivatives that include palmitoylethanolamide and oleamide, which can potentiate anandamide, and 2-linoleoylglycerol and 2-palmitoylglycerol, which can potentiate 2-arachidonylglycerol. 37 The mechanism(s) underlying the entourage effect have yet to be established.
Endocannabinoids most probably have both neuromodulatory and immunomodulatory roles that generated. 36 include inhibition of ongoing transmitter release through retrograde signaling 38 and regulation of cytokine release and of immune cell migration. 39,40 It is also now generally accepted that there are certain disorders in which endocannabinoid release the co-release of other endogenous fatty acid increases in particular tissues, and secondly, that this upregulation of the endocannabinoid system leads in some instances to the suppression of unwanted signs and symptoms and so is "autoprotective" and in others to the production of undesirable effects. 5 Thus for example, there is evidence that endocannabinoid release on the one hand ameliorates spasticity in multiple sclerosis and inflammatory pain and on the other hand contributes towards obesity n some individuals or impairs fertility in certain women. As a result, there is now enormous interest not only in directly acting cannabinoid receptor agonists and antagaonists but also in compounds that can affect the activity of the endocannabinoid system indirectly by allosterically modulating endocannabinoid —induced activation of cannabinoid receptors or by altering the concentration of endocannabinoids at their receptors through effects on endocannabinoid production or fate. The remainder of this review describes the main pharmacological actions of a number of such direct and indirect cannabinoid receptor agonists and antagonists. It focuses particularly on those compounds that are most widely used in cannabinoid research as experimental tools. Whenever possible, previous review articles have been cited that provide more detailed information and list additional references.
For full article: CB1 receptor : CB2 receptor