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Cannabinoid Receptor Ligands

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Cannabinoid Receptor Ligands CANNABINOID RECEPTOR LIGANDS Professor R. G. Pertwee The central distribution pattern of CB1 receptors is Department of Biomedical Sciences, Institute heterogeneous and accounts for several prominent of Medical Sciences, University of Aberdeen, pharmacological properties of CB1 receptor agonists, Foresterhill, Aberdeen AB25 2ZD, Scotland for example their ability to impair cognition and Roger Pertwee is Professor of memory and to alter the control of motor function. Neuropharmacology at the University of Aberdeen. Thus the cerebral cortex, hippocampus, lateral His research interests include the pharmacology of caudate-putamen, substantia nigra pars reticulata, cannabinoid receptors, the physiological and globus pallidus, entopeduncular nucleus and the pathophysiological roles of endogenous molecular layer of the cerebellum are all populated cannabinoid receptor ligands, and the therapeutic with particularly high concentrations of CB1 potential of cannabinoids. receptors.12,18 In line with the analgesic properties of cannabinoid receptor agonists, CB1 receptors are also found on pain pathways in brain and spinal cord and The endocannabinoid system at the peripheral terminals of primary sensory 14 neurones. Although the concentration of CB1 Two types of cannabinoid receptor have so far been receptors is considerably less in peripheral tissues 1 than in the central nervous system, this does not imply identified, CB1 , cloned in 1990, and CB2 , cloned in 1993.2 These have now been detected in several that peripheral CB1 receptors are unimportant. This is species including man, rat and mouse3 and both CB because some peripheral tissues may contain high 1 concentrations of CB receptors, localized in discrete and CB2 receptor knockout mice have been 1 4-6 regions such as nerve terminals that form only a small developed. The CB1 receptors of different mammalian species exhibit a high level of similarity. part of the total tissue mass. Peripheral tissues in which CB receptors are expressed on neurones For example, CB1 nucleotide sequences of human 1 and rat are 90% identical, those of human and mouse include the heart, vas deferens, urinary bladder and 91% identical and those of rat and mouse 96% small intestine.12 identical.7,8 CB receptors show greater interspecies 2 12,19 differences, the deduced amino acid sequence of the As detailed elsewhere, both CB12 and CB receptors are coupled through G proteins, negatively mouse CB2 receptor differing from that of the human i/o 9 to adenylate cyclase and positively to mitogen- CB2 receptor in 60 residues (82% similarity). These differences are apparent mainly in the N-terminal activated protein kinase. In addition, CB1 receptors are coupled to ion channels through G proteins, extramembrane region. A spliced variant of CB1 i/o cDNA, CB , has also been isolated.10,11 However, positively to A-type and inwardly rectifying potassium 1a channels and negatively to N-type and P/Q-type CB1a mRNA exists only as a minor transcript and there is no evidence for any notable difference between the calcium channels and to D-type potassium pharmacology of CB and CB receptors. channels.12,19,20 The coupling to A-type and D-type 11a potassium channels is thought to be through adenylate cyclase.20,21 Inwardly rectifying potassium CB1 mRNA has been detected both in the central nervous system and in certain peripheral tissues channels can also serve as a signalling mechanism including pituitary gland, immune cells, reproductive for the CB2 receptor, at least inXenopus oocytes that tissues, gastrointestinal tissues, superior cervical have been transfected with such channels together ganglion, heart, lung, urinary bladder and adrenal with this receptor type.22,23 In addition, there is 12 evidence from experiments with rat hippocampal CA1 gland. Some CB1 receptors are located at central and peripheral nerve terminals12,13,14 and, when pyramidal neurones that CB1 receptors are negatively 24 activated, these receptors seem to suppress the coupled to M-type potassium channels. CB1 neuronal release of one or other of a range of receptors may also mobilize arachidonic acid and 12 excitatory and inhibitory transmitters that include close 5-HT3 receptor ion channels and, under certain acetylcholine, noradrenaline, dopamine, 5 hydroxy- conditions, couple to Gs proteins to activate adenylate 25,26 tryptamine,g -aminobutyric acid, glutamate and cyclase and/or to reduce outward potassium K aspartate.14 CB mRNA is present mainly in immune current, possibly through arachidonic acid-mediated 2 27 cells with particularly high levels in B-cells and natural stimulation of protein kinase C. The questions of killer cells.15 Little is yet known in any detail about the whether CB1s receptor coupling to G proteins has physiological importance and of whether such physiological or pathophysiological roles of CB2 receptors. Most likely, these include coupling increases after Gi/o protein sequestration by immunomodulation which may depend at least in part co-localized non-cannabinoid Gi/o protein-coupled receptors have yet to be resolved. CB1 receptors have on CB2 receptor-mediated suppression of proinflammatory cytokine release and enhancement of also been reported to be positively coupled to antiinflammatory cytokine release from immune phospholipase C through G proteins in COS7 cells co- 22 16,17 transfected with CB1 receptors and Ga subunits and cells. Thus one major role that CB1 and CB2 receptors may have in common is modulation of negatively coupled to voltage-gated L-type calcium ongoing release of chemical messengers. channels in cat cerebral arterial smooth muscle Tocris Cookson Ltd., UK Tocris Cookson Inc., USA Tel: + 44 (0)117 982 6551 Toll Free Tel: (800) 421-3701 Tel: (636) 207-7651 Fax: + 44 (0)117 982 6552 Toll Free Fax: (800) 483-1993 Fax: (636) 207-7683 e-mail: [email protected] e-mail: [email protected] e-mail: [email protected] 28 cells. One other recent finding is that CB1 receptors chemical groups: classical, nonclassical, on cultured cerebellar granule neurones can operate aminoalkylindole and eicosanoid,45 (Figures 1 and 2 through a phospholipase C-sensitive mechanism to and Table 1). Classical cannabinoids consist of enhance NMDA-elicited calcium release from inositol dibenzopyran derivatives and are either plant-derived 1,4,5-triphosphate-gated intracellular stores.29 cannabinoids or their synthetic analogues. The most investigated of these include the psychotropic plant The discovery of cannabinoid receptors was followed cannabinoids,DD99 -tetrahydrocannabinol ( -THC) and in 1992 by the demonstration that arachidonoyl D8-THC, and the synthetic cannabinoid, 11-hydroxy- ethanolamide (anandamide) is an endogenous ligand D8-THC-dimethylheptyl (HU-210). The nonclassical for these receptors.30 Other endogenous cannabinoids cannabinoids were developed by a Pfizer research (endocannabinoids) have since been identified, of team.48 They are quite similar in structure to classical which the most important is 2-arachidonoyl glycerol.31-33 cannabinoids, consisting as they do of bicyclic and Both anandamide and 2-arachidonoyl glycerol tricyclic analogues ofD9 -THC that lack a pyran ring. undergo depolarization-induced synthesis/release Important examples are CP 55940, CP 55244, from neurones and are removed from the extracellular CP 50556 (L-nantradol) and desacetyl-L-nantradol. space by a carrier-mediated, saturable uptake process The aminoalkylindole group was developed by a that is present in the membranes of neurones and Sterling Winthrop research team,49,50 the prototype of 31,34-37 astrocytes. There is also evidence that this group being WIN 55,212-2 (R -(+)-WIN55212). anandamide release in rat dorsal striatum can be This group contains compounds that are structurally triggered by the activation of dopamine D , D and/or 23 quite different from classical or nonclassical D receptors.38 Once within the cell, anandamide is 4 cannabinoids and, indeed, there is evidence that WIN hydrolysed to arachidonic acid and ethanolamine by 55,212-2 binds differently to the CB receptor than 31,36,39 1 fatty acid amide hydrolase (FAAH). FAAH can classical and nonclassical cannabinoids, albeit it in a also catalyse the hydrolysis of 2-arachidonoyl manner that still permits mutual displacement between 31,40 glycerol, an indication that it has esterase as well WIN 55,212-2 and non-aminoalkylindole cannabinoids as amidase activity. The distribution in rat brain of 45 at CB12 and CB binding sites. The prototypic FAAH immunoreactivity is heterogeneous, as is the member of the eicosanoid group of cannabinoid brain distribution of FAAH mRNA and FAAH receptor agonists is the endocannabinoid, enzymatic activity. In line with the putative roles of anandamide (see above). Cannabinoid receptor anandamide and 2-arachidonoyl glycerol as agonists often contain chiral centres and these endogenous cannabinoids, these measures of FAAH generally confer marked stereoselectivity in brain distribution exhibit considerable though not pharmacological assays. WIN 55,212-2 is more active complete overlap with the brain distribution of CB 1 than WIN 55,212-3 (S -(-)-WIN55212) and classical 34,39,41-43 receptors. Unlike the endocannabinoid and nonclassical cannabinoids with the same absolute membrane transporter, which remains to be fully stereochemistry as (-)-D9 -THC at 6a and 10a (6aR , characterized, FAAH has been cloned44 and FAAH 10aR ) have the greater activity. Anandamide itself knockout mice developed (personal communication does not
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