SYNTHESIS AND PHARMACOLOGICAL COMPARISON OF DIMETHYLHEPTYL AND PENTYLANALOGS OF ANANDAMIDE

(Dimethylheptyl)anandamide ethyldocosa-cis-5,8,11,14-tetraenoyl)ethano lamine] (17a) and its amide analogs were synthesized by Wittig couplin g of a ylide derived from a fragment of arachidonic acid. These amides were compared to the endogenous cannabinoid receptor ligand arachidon ylethanolamide (anandamide, 2a) and its amide analogs in pharmacologic al assays for potential enhancement of cannabimimetic activities. The receptor affinity to rat brain membranes of the dimethylheptyl (DMH) a nalogs increased by an order of magnitude in most comparisons to the c orresponding anandamides in displacement assays versus the cannabinoid agonist [H-3]CP 55,940 or antagonist [H-3]SR141716A, for which rank o rder differences in affinity were observed. An order of magnitude enha ncement of potency with comparable or higher efficacy in behavioral as says in the mouse tetrad of tests of cannabinoid activity was observed in 17a versus 2a. In contrast, no enhancement in potency for the pent yl to DMH side chain exchange was seen in the mouse vas deferens assay . The data indicate a structural equivalence between classical plant c annabinoids and 2a as well as different receptor-ligand interactions t hat characterize multiple receptor sites or binding modes.