Endogenous and Synthetic Cannabinoids: Recent Advances

Abstract

In this review we present a summary of recent results on the action of cannabinoids endogenous to the central nervous system (CNS; the anandamides) and peripheral tissues (2-arachidonoyl-glycerol 2-Ara-GI), as well as two synthetic cannabinoids, HU-2 10, a highly potent cannabinoid agonist, and its enantiomer, HU-2 1 I , an N-methyl-D-aspartate (NMDA) antagonist that lacks cannabinoid activity.The major psychoactive constituent of Cannabis sativa, A9-tetrahydrocannabinol (THC), was first isolated in pure form and its structure elucidated by our group in 1964 (49). Shortly thereafter, its stereochemistry was established ( Fig. 1) (80), and several total syntheses were achieved (79,102). These advances and the public interest in Cannabis, in particular during the "flower years" of the 1960s and 197Os, led to extensive research that clarified to a large extent many aspects of cannabinoid action such as its metabolism, physiological and pharmacological effects, and various clinical and therapeutic aspects (28,74,85,99). It was not until 1988, however, that a major breakthrough in our understanding of the mode of action of cannabinoids was achieved with the identification and, shortly thereafter the cloning, of a cannabinoid receptor (now designated CB,) in brain and in neuroblastoma cells (25,76). In 1993 a second receptor (CB2) was found to be present in spleen (88). Various structural and biochemical aspects of CBI and CB2 have been reviewed in a recent book (98) and in detailed reviews (31,57,75). While CBI is found mostly in the brain, its RNA has also been detected in some peripheral tissues (21,2930). CB2 and its RNA have been detected only in cells of the immune system (39,88).

The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation

“…Anandamide also displaced [ 3 H]CP-55,940 binding from MCF-7 cell membranes (data not shown). We have not investigated the reasons why SR 141716A exerted a slight anti-proliferative action or why HU-210, as opposed to what previously has been observed for this compound (34), was less active than anandamide in binding assays with EFM-19 cell membranes. It is possible that some HBC lines express a CB1-like variant whose interactions with SR 141716A and HU-210 are slightly different from those described for CB1 receptors.…”

“…Therefore, we next wanted to determine whether anandamide anti-mitogenic action was due to interaction with selective binding sites or rather to noncannabinoid receptor-mediated intracellular effects (13,28). We found that a synthetic cannabinoid, HU-210 (34), as well as another endogenous ligand of cannabinoid receptors, 2-arachidonoyl-glycerol (8, 9), but not an anandamide congener, palmitoylethanolamide [which is inactive at CB1 receptors (28,34)], also exhibited a potent anti-proliferative action on EFM-19 cells (Fig. 2a), thus suggesting that this effect is due to interaction with cannabinoid receptors.…”

N-Acylethanolamines in human reproductive fluids

“…Additional cannabinoid receptor subtypes may exist (Pertwee, 1999;Kunos and Batkai, 2001). AEA and 2-AG have higher affinity for CB1 than for CB2 receptors (Khanolkar et al, 1996;Shohami et al, 1996), but differ in their efficacy to elicit a signal via these receptors (Breivogel and Childers, 2000;Gonsiorek et al, 2000;Hillard, 2000). PEA can act as an entourage compound by protecting other NAEs from enzymatic hydrolysis Lambert and Di Marzo, 1999;Di Marzo et al, 2001b;Jonsson et al, 2001).…”

Theoretical study of the hydrophobic character of the dimerization of dexanabinol

“…Dexanabinol (HU‐211), a (+)‐3s, 4s enantiomer of a tetrahydrocannabinol derivative, has only negligible affinity for the cannabinoid central (CB1) receptor, but it is a noncompetitive N ‐methyl‐ D ‐aspartate (NMDA) receptor antagonist and retains glutamate cascade cytoprotective action1, 2. Earlier research demonstrated that HU‐211 protects neurons from neurotoxicity induced by excess concentrations of the excitatory neurotransmitter glutamate.…”

“…Excess release of glutamate, which acts by binding to the NMDA receptor, is associated with trauma and disease 3. As an NMDA antagonist, HU‐211 blocks the damaging action of glutamate and other endogenous neurotoxic agents2, 4–6. Dexanabinol is an extremely lipophilic compound and has low solubility in water.…”