Current Pharmaceutical Design - Volume 6, Issue 13, 2000

Research leading to the isolation of the plant cannabinoids during the 1960s and to the endogenous cannabinoids, during the 1990s is described. Investigations on two non-psychotropic, synthetic cannabinoids, HU-211, a neuroprotective agent and HU-308, a specific CB 2 agonist are presented.

Following the identification of the CB2 receptor several groups explored the development of selective ligands for this receptor which occurs principally in the periphery. This led to the discovery that two cannabimimetic indoles, 1-(2,3-dichlorobenzoyl)- 2-methyl-3-(2-[1-morpholino]ethyl)-5-methoxyindole (L768242) and 2-methyl-1-propyl-3-(1-naphthoyl)indole (JWH-015) have high affinity for the CB2 receptor with low affinity for the CB1 receptor. Shortly thereafter two 1- methoxy-Delta 8 -THC analogues, 1-methoxy-Delta 8 -THC-DMH (L759633) and 1-methoxy-Delta 9(11) -THC-DMH (L759656), were also found to have high affinity for the CB2 receptor and very little affinity for the CB1 receptor. Almost simultaneously two 1-deoxy-Delta 8 -THC analogues, 1-deoxy-11-hydroxy-Delta 8 -THC-DMH (JWH-051) and 1-deoxy-Delta 8 -THC-DMH (JWH-057) were reported to have high affinity for the CB1 receptor, but even greater affinity for the CB 2 receptor. These discoveries gave rise to a concerted effort by Huffman and co-workers to explore the structure-activity relationships (SAR) at CB2 of cannabimimetic indoles and 1-deoxy-Delta 8 -THC analogues. These efforts have resulted in the synthesis and pharmacological evaluation of a number of derivatives of 3-(1-naphthoyl)indoles and 1-deoxy-Delta 8 -THC analogues with various side chains. This review will describe the current status of the results of these studies and discuss the SAR for both these classes of ligands.

The acid metabolites of THC were discovered almost 30 years ago and were later shown to posses modest analgesic and anti-inflammatory activity in a variety of models. Ajulemic acid (CT3) is a more potent analog of THC-11-oic acid in which a dimethylheptyl side chain is substituted for the pentyl side chain of the naturally occurring metabolite. It produces analgesia in the mouse hot plate, the PPQ writhing, the formalin and the tail clip assays. In the latter, it was equipotent to morphine; however, it showed a much greater duration of action. In the paw edema, subcutaneous air pouch and rat adjuvant-induced arthritis models of inflammation; it showed significant therapeutic activity at a dose of 0.2 mg/kg p.o. In the arthritis model it greatly reduced permanent damage to joints when compared to an indomethacin control as evidenced by an improved joint score over vehicle controls and by histopathological examination. In contrast to the NSAIDs, it was totally nonulcerogenic at therapeutically relevant doses. Moreover, it does not depress respiration, exhibit dependence, induce body weight loss or cause mutagenesis. It shows none of the typical actions in models of the psychotropic actions of cannabinoids suggesting that a good separation of desirable from undesirable effects was achieved. Studies on its mechanism of action are currently underway. The data thus far suggest the existence of a novel receptor for ajulemic acid with possible downstream effects on eicosanoid production, cytokine synthesis and metalloprotease activity. There is also circumstantial evidence for a putative endogenous ajulemic acid, namely, arachidonylglycine.

Unlike natural cannabinoids which belong to the 6aR - trans series, the synthetic dexanabinol (HU-211), a 6aS-trans enantiomer, does not have affinity toward cannabinoid receptors and is devoid of cannabimimetic activity. On the other hand, dexanabinol demonstrated significant neuroprotective properties which prompted its development as a therapeutic agent. We now present the extension of a series of 6aS-trans cannabinoids with novel derivatives, including water soluble derivatives and congeners of dexanabinol.

The possible therapeutic use of marijuanas active principles, the cannabinoids, is currently being debated. It is now known that these substances exert several of their pharmacological actions by activating specific cell membrane receptors, the CB 1 and CB 2 cannabinoid receptor subtypes. This knowledge led to the design of synthetic cannabinoid agonists and antagonists with high therapeutic potential. The recent discovery of the endocannabinoids, i.e. endogenous metabolites capable of activating the cannabinoid receptors, and the understanding of the molecular mechanisms leading to their biosynthesis and inactivation, opened a new era in research on the pharmaceutical applications of cannabinoids. Ongoing studies on the pathological and physiological conditions regulating the tissue levels of endocannabinoids, and on the pharmacological activity of these compounds and their derivatives, may provide a lead for the development of new drugs for the treatment of nervous and immune disorders, cardiovascular diseases, pain, inflammation and cancer. These studies are reviewed in this article with special emphasis on the chemical features that determine the interaction of endocannabinoids with the proteins mediating their activity and degradation.

The identification of arachidonylethanolamide (anandamide, AEA) as an endogenous cannabinoid has been an important development in cannabinoid research which has led to the identification of two proteins associated with cannabinoid physiology in addition to the CB1 and CB2 receptors. These proteins are anandamide amidohydrolase (AAH), an enzyme responsible for the hydrolytic breakdown of anandamide and the anandamide transporter (ANT), a carrier protein involved in the transport of anandamide across the cell membrane. Evidence obtained so far suggests that these two proteins, in combination, are responsible for the termination of the biological actions of anandamide. Also, the discovery of anandamide has revealed a novel class of more selective agents possessing somewhat different pharmacological properties than the cannabinoids. A number of such analogs have now been reported many of which possess markedly improved cannabinoid receptor affinities and metabolic stabilities compared to those of the parent ligand. Generally, anandamide and all known analogs exhibit significant selectivities with high affinities for the CB1 receptor and modest to very low affinity for the CB2 receptor. In a relatively short period of time, pharmacological and biochemical studies have confirmed initial speculations that anandamide is either a neuromodulator or neurotransmitter and has significantly advanced our understanding of cannabinoid biochemistry. This summary seeks to define the pharmacology of endocannabinoids and to focus on the structure-activity relationships (SAR) of anandamide for the CB1 cannabinoid receptor.