The Cannabinoid Receptors

FIGURE 2.7 A helix net representation of the human CB, receptor sequence. 

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Gannabinoids. Like the BZ receptor, the cannabinoid receptor was initially identified using psychotropic alkaloids such as A -tetrahydrocannabinol (A-THC) (78) that were known to affect mammalian CNS function (see PsYCHOPHARMACOLOGiCALAGENTs). The CNS receptor,... 

A natural sythesised cannabinoid interacting with the cannabinoid receptor I and II. In addition, anandamide blocks receptor-independent all LVA-calcium channels. 

Braida D, Pozzi M, Cavallini R, et al Intracerebral self-administration of the cannabinoid receptor agonist CP 55,940 in the rat interaction with the opioid system. EurJ Pharmacol 413 227-234, 2001... 

Martellotta MC, Cossu G, Fattore L, et al Self-administration of the cannabinoid receptor agonist WIN 55,212—2 in drug-naive mice. Neuroscience 85 327—330, 1998... 

CP-55,940 (8.5) was developed during the search for novel analgesics [146]. Although it is more potent than morphine it was never approved. Nevertheless, in its tritium-labeled form it became a very important tool for research and helped in the first identification of the cannabinoid receptor. 

In the search for new anti-inflammatory drugs structurally derived from indomethacine [147], Pravadoline showed psychotropic side effects in clinical trials. It became apparent that these effects are mediated through the cannabinoid receptor. Optimization of the structure Anally led to WIN-55,212-2 (8.6), which has a higher affinity to the CBl receptor than THC [148]... 

HU-210 is (8.1) among the most potent cannabinoids known. Its enantiomer HU-211 (8.2) does not bind to the cannabinoid receptor and lacks psychotropic side effects (as long as optical purity is guaranteed). In animal models it shows analgesic and antiemetic activity. It also shows neuroprotec-tive effects after brain injury and was tested in humans as anti-traiuna agent, where it did not meet the expectations in a clinical phase III trial. 

Since the cloning of the cannabinoid receptors, their endogenous ligands, the endocannabinoids, have received a great deal of research interest. A number of recent review articles have extensively covered the end-ocannabinoid system [10-12], so the coverage in this article will be brief. 

The best studied of the endocarmabinoids are anandamide (A -arachidonyl-ethanolamine, AEA)(1) and 2-arachidonylglycerol (2-AG)(2). Anandamide was first identified from porcine brain extracts by Devane and co-workers in 1992 [13], while 2-AG was first reported in 1995 to have been isolated from canine gut [14] and rat brain [15]. More recently, noladin ether (2-arachidonyl-glyceryl ether, 2-AGE)(3) [16], virodhamine (D-arachidonyl-ethanolamine)(4) [17] and A-arachidonyl-dopamine (NADA)(5) [18] were proposed as endogenous ligands for the cannabinoid receptors. In a subsequent publication, the authors failed to detect noladin ether in mammalian brains and questioned the relevance of this compound as an endocarmabinoid [19]. Anandamide, noladin ether and NADA have functional selectivity for CBi receptors, virodhamine is CB2 selective and 2-AG is essentially non-selective. 

The discovery of the cannabinoid receptors and their G-protein-coupled nature strongly suggested the existence of endogenous cannabimimetic... 

Crawley JN, Corwin RL, Robinson J, Felder CC, Derane WA, Axelrod J. Anandamide, an endogenous ligand of the cannabinoid receptor, induces hypomotility and Hypothermia in vivo in rodents. Pharmacol Biochem Behav 1993 46 967-972. 

D Ambra K, Estep G, et al. Conformational restricted analogues of pra-vadoline nanomolar potent, enanantioselective, (aminoalkyl)indole agonists of the cannabinoid receptor. J Med Chem 1992 35 124—135. 

Deutsch DG, Lin S, Hill WAG, Morse KL, Salehani D, Arreaza G, Omeir RL, Makriyannis A. Fatty acid sulfonyl fluorides inhibit anandamide metabolism and bind to the cannabinoid receptor. Biochem Biophys Res Com-mun 1997 231 217-221. 

Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptors. Science 1992 258 1946-1949. 

Devane WA, Axelrod J. Enzymatic synthesis of anandamide, an endogenous ligand for the cannabinoid receptor, by brain membranes. Proc Natl Acad Sci USA 1994 91 6698-6701. 

Fride E, Mechoulam R. Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. Eur J Pharmacol 1993 231 313-314. 

Hampson, AJ, Hill WA, Zan Phillips M, Makriyannis A, Leung E, Eglen, RM, Bornheim LM. Anandamide hydroxylation by brain lipoxygenase metabolite structures and potencies at the cannabinoid receptor. Biophys. Biochim. Acta 1995 1259 173-179. 

Hanus L, Gopher A, Almog S, Mechoulam R. Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor. J Med... 

Khanolkar AD, Palmer SL, Makriyannis A. Molecular probes for the cannabinoid receptors. Chem Phys Lipids 2000 108 37-52. 

Devane WA, Breuer A, Sheskin T, Jarbe TU, Eisen MS, Mechoulam, R. A novel probe for the cannabinoid receptor. J Med Chem 1992 35 2065-2069. 

Gifford AN, Tang Y, Gatley SJ, Volkow ND, Lan R, Makriyannis A. Effect of the cannabinoid receptor SPECT agent, AM 281, on hippocampal acetylcholine release from rat brain slices. Neurosci Lett 1997 238 84-86. 

Gifford AN, Ashby CR. Electrically evoked acetylcholine release from hippocampal slices is inhibited by the cannabinoid receptor agonist, WIN 55212-2, and is potentiated by the cannabinoid antagonist, SR 141716A. J Pharmacol Exp Ther 1996 277 1431-1436. 

The cellular actions of cannabinoids clearly support the proposal that the cannabinoid receptor is inhibitory and, consequently, reduces the firing rate of target neurons. However, this is not wholly confirmed by electrophysiological measurements, which suggest that cannabinoid compounds can stimulate neurons in the hippocampus. This apparent discrepancy may be due to the ability of cannabinoids to inhibit the release of an inhibitory substance in the hippocampus and, thus, produce a net excitation. 

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