Cannabinoids and their derivatives exert their effects via "central" CB1 receptors, mostly expressed in brain and responsible for cannabinoid psychoactivity, and "peripheral" CB2 receptors, mostly expressed in the immune system and unrelated to cannabinoid psychoactivity. In addition to these receptors the cannabinoid system is comprised of various endogenous ligands such as anandamide (AEA), 2-arachidonoylglycerol, 2-arachidonyl glyceryl ether, and the recently reported virodhamine; and an inactivation system that degrades these endocannabinoids. This termination system consists of the uptake of anandamide followed by its intracellular metabolism by fatty acid amidohydrolase. Control of this pathway is key due to its involvement in numerous physiological processes including antinociception, memory, control of movement, cardiovascular and immune regulation, and cellular proliferation. Correspondingly, molecules that modulate this pathway represent therapeutic candidates in the treatment of hyperalgesia, neurodegenerative disorders, and tumor progression.

The anandamide transporter represents one molecular target for the therapeutic control of the cannabinoid pathway and hence Maria López-Rodríguez and colleagues have recently conducted a study to identify the molecular requirements of molecules able to act as substrates for the transporter. In particular they have developed a new series of arachidonic acid derivatives, in which the ethanolamine moiety of anandamide was replaced with a fragment containing a heterocyclic ring. This series was found to inhibit anandamide uptake with high potency and selectivity. Extensive SAR studies have been conducted to optimize the nature of the heterocyclic ring and the linker region between the ring and the arachidonate moiety. These studies have produced molecules with sub-micromolar affinity for the transporter and with impressive selectivity compared to fatty acid amidohydrolase and the cannabinoid receptors.

At a dose that did not produce any effects by itself, the lead compound from this series (UCM-707) was able to confer hypokinetic and analgesic activity to sub-threshold doses of anandamide (de Lago et al, 2002). This suggests that UCM-707 or its derivatives may be of use in the treatment of movement disorders. Tics in Tourette syndrome, the levodopa-induced dyskinesia in Parkinson’s disease and some forms of tremor and dystonia have already been suggested to benefit from the use of cannabinoid agonists. Inhibitors of the anandamide transported may have an improved therapeutic window compared to such molecules under these conditions. Likewise inhibitors of the anandamide transporter may also be of benefit in the treatment of hyperalgesia.

Entry date Wednesday, July 02, 2003

Adapted from Lopez-Rodriguez et al, J Med Chem. 2003 46(8):1512-22.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk