Cannabimimetics

CP 55940 (79) and nabilone (80) are synthetic ligands for the cannabiaoid receptor. However, the identification of the eicosanoid, anandamide (81), as an endogenous cannabimimetic has provided an important tool to study cannabiaoid receptor function. 

Following on from this, and to further exemplify this pharmacophore model, Huffman [182] described a novel hybrid structure that combined the hydroxydibenzopyran ring of THC and the indole moiety of the AAIs into one molecule. It was found that the hybrid molecule (270) had a similar affinity (19 nM) for the CBi receptor in vitro as (67) (41 nM). The compound was also active in vivo in the mouse tetrad model of cannabimimetic activity and had comparable potency to (67) [182]. 

Beyond this relatively limited medical use of cannabimimetics, the current, albeit long-delayed elucidation of their pharmacology is likely to lead to a wide expansion of the clinical potential and significance of... 

The advent of synthetic cannabimimetics with a high degree of enantioselectivity (Johnson, 1986 Little, 1988) paved the road for the identification of specific cannabinoid binding sites in rat brain (Devane, 1988). This discovery marked the onset of a revolution in the understanding of cannabinoid biology. 

Mouse vas deferens (MVD) seems to express CB1 and at least one CB2-like cannabinoid receptor type, as is demonstrated by the presence of CB1 and CB2-like mRNA as well as by data collected from experiments with cannabinoid receptor selective agonists and antagonists (Pertwee, 1999). Furthermore, evidence indicates that a CBl-like receptor exists in vascular endothelium, which upon activation produces significant hypotension (Wagner, 1999). This receptor differs from CB1 in its pharmacological response to some well-characterized cannabimimetics. 

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

In addition to anandamide, several other endogenous polyunsaturated fatty acid derivatives were also found to act as cannabimimetics. They are all now collectively referred to as endocannabinoids. Soon after the discovery of anandamide, two more fatty acid ethanolamides were isolated and found to bind to CB1 preparations with affinities similar to that of anandamide (anandamide CB1 binding affinity K = 39.2 nM, according to Hanus et al., 1993). These were the homo-y-linolenylethanol-amide (CB1 K[ = 53.4 nM) and 7,10,13,16-docosatetraenylethanolamide (CB1 K[ = 34.4 nM) (Fig. 2). All three V-acylethanolamide endocannabinoids were found to be CB1 agonists in the MVD test (Pertwee, 1994). 

Later 2-AG was also found in the brain (Stella, 1997) and spleen (Di Marzo, 1998). It was shown to be released in a calcium-dependent manner, reaching concentrations 170 times higher than that of anandamide in the brain (Stella, 1997). Like the other endocannabinoids, 2-AG was shown to produce the typical tetrad of cannabimimetic behavioral effects and inhibit electrically evoked contractions of mouse MVD (Mechoulam, 1995a). 

Anandamide, in vivo, was shown to produce the four characteristic effects of cannabimimetics, namely, analgesia, hypothermia, hypoactiv-ity, and catalepsy (Smith, 1994 Fride, 1993 Crawley, 1993). These four effects are not unique to cannabimimetics when they are produced together, however, they are highly predictive of cannabimimetic activity (Martin, 1991). Anandamide was found to be less potent than delta-9-THC in producing these behavioral effects in mice (Fride, 1993). It has quicker onset and shorter duration of action, the latter because of rapid catabolism. Cross-tolerance studies, in which pretreatment of mice with delta-9-THC produced tolerance to most of the pharmacological effects of anandamide and vice versa, indicate that both drugs act on the same receptor (Jarbe, 1998). 

Many classical cannabinoid analogs have been synthesized and evaluated pharmacologically and biochemically (Razdan, 1986 Mechou-lam, 1999). The CC structural features that seem to be important for cannabimimetic activity (Makriyannis, 1990) are as follows ... 

Most known cannabimimetics today have very broad effects on organ systems, several of which are still not completely delineated. The ubiquitous pharmacology of cannabimimetics is one of the reasons for the failure, thus far, of the clinical application of these drugs to reach its full potential. The sections that follow summarize the effects of cannabinergics on the various physiological systems and the possible therapeutic uses that may arise from these biological activities. 

The primary system of cannabimimetic activity is the nervous system. The CB1 receptor is omnipresent in the brain, especially in areas that control functions affected by cannabimimetics. One of the functions most pronouncedly influenced by cannabimimetics is motor behavior. Catalepsy, immobility, ataxia, and impairment of complex behavioral acts after acute administration of high doses of cannabimimetics are manifestations of such motor effects (Pertwee, 1997). In lower doses cannabimimetics produce the opposite effects. The very dense presence of CB1 in the cerebellum and the basal ganglia, areas responsible for motor activity, is... 

The CB1 receptors present in the hippocampus, amygdala, and cerebral cortex may be responsible for observations that cannabimimetics are effective against some types of seizures (Consroe, 1998). The anticonvulsant and antispastic effects of cannabinoids are well documented, however the mechanisms of these effects are still unclear (Nahas, 1999). 

Another significant cannabinoid activity that is mediated by the nervous system arises from the antinociceptive properties of these agents. Compelling evidence suggests that cannabimimetics are effective in the... 

A second current clinical indication of cannabimimetics is their antiemetic and antinausea effects, especially in cancer chemotherapy patients. These effects are mediated above the level of vomiting reflex and possibly through descending inhibitory connections to the lower brain stem centers (Levitt, 1986). 

Cannabimimetics are also shown to affect reproductive and metabolic functions indirectly by hormonal modulation through the hypothalamic and pituitary regulatory centers. They are found to reduce serum levels of the luteinizing hormone, prolactin, growth hormone, and thyroid-stimulating hormone, and to increase corticotropin (Murphy, 1998). 

Cannabimimetics reduce the intestinal motility by a CB1-mediated inhibitory activity on acetylcholine release from autonomic fibers. An endo-cannabinoid, 2-AG, was isolated from dog intestine however, its role there remains unknown (Mechoulam, 1995a). 

Huffman JW, Dai D, Martin BR, Compton DR. Design, synthesis and pharmacology of cannabimimetic indoles. Bioorg Med Chem Lett 1994 4 563-566. 

Xie X-Q, Eissentat M, Makriyannis A. Common cannabimimetic phar-macophoric requirements between aminoalkylindoles and classical cannabinoids. Life Sci 1995 56 1963-1970. 

Felder CC, Briley EM, Axelrod J, Simpson JT, Mackie K, Devane WA. Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction. Proc Natl Acad Sci USA 1993 90 7656-7660. 

Koe BK, Milne GM, Weissman A, Johnson MR, Melvin LS. (1985). Enhancement of brain [3H]flunitrazepam binding and analgesic activity of synthetic cannabimimetics. EurJ Pharmacol. 109(2) 201-12. 

Its hypnotic properties were characterized. Its mechanism of action is far from being understood. Although it does not bind with high affinity to CB] or CB2 receptors, it exhibits some cannabimimetic actions, which could be explained at least in part by entourage effects. It is likely that oleamide and anandamide have common as well as distinct pathways of action. The 5-HT2A receptor appears to be a target for oleamide but the possibility of the existence of specific receptors for this compound is still open. Legget et have reported that oleamide is a full cannabi-... 

Hewlett AC, Qualy JM, Khachatrian LL, Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic dtvegs. Mol Pharmacol 29 307—313, 1986. 

Lambert DM, Di Marzo V, The palmitoylethanolamide and oleamide enigmas Are these two fatty acid amides cannabimimetic Curr Med Chem 6 757-773, 1999. 

Analogous to the discovery of the endogenous opiates and opiate receptors, the discovery of cannabinoid receptors in 1988 suggested the presence of endogenous cannabimimetic compounds. In 1992 anandamine—the ethanolamide of arachidonic acid was purified from porcine brain and shown to behave... 

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