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JC Pinto, F Potie, KC Rice, D Boring, MR Johnson, DM Evans, GH Wilken, CH Cantrell and AC Howlett
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
The cannabinoid receptor in brain (CB1) specifically binds delta 9- tetrahydrocannabinol, the predominant central nervous system-active component of marijuana. An eicosanoid found in brain, N-(2- hydroxyethyl)arachidonylamide (anandamide), binds to CB1 with similar affinity. This report considers structure-activity requirements for a series of novel amides and rigid hairpin conformations typified by N-(2- hydroxyethyl)prostaglandin amides, assayed with phenylmethylsulfonyl fluoride inactivation of esterases/amidases. Arachidonyl esters were 30- fold less potent than N-(2-hydroxyethyl)arachidonylamide, showing a rank order of potency of methyl = ethyl > propyl = isopropyl. Within the N-(hydroxyalkyl)arachidonylamide series, a one-carbon increase in chain length increased the potency 2-fold, but continued extension decreased affinity. Substituting the amide for the N-(2- hydroxyethyl)amide function produced a 4-fold loss of affinity. The N- (propyl)-, N-(butyl)-, and N-(benzyl)arachidonylamide derivatives exhibited a 3-fold increase, no change, and a 5-fold decrease, respectively, in affinity, compared with N-(2- hydroxyethyl)arachidonylamide. Both the methoxy ether and the formamide derivatives suffered > 20-fold loss of potency, compared with N-(2- hydroxyethyl)arachidonylamide. N-(2-Aminoethyl)arachidonylamide interacted poorly with CB1. At 100 microM, N-(2-hydroxyethyl)amide analogs of prostaglandin E2, A2, B2, and B1 failed to alter [3H]CP55940 binding to CB1. N-(2-Hydroxyethyl)arachidonylamide inhibited adenylate cyclase with lesser potency but with similar efficacy, compared with desacetyllevonantradol. Extending the length of the hydroxyalkyl moiety by one carbon increased the apparent potency by 1 order of magnitude. The N-(propyl) derivative exhibited a 5-fold greater potency than did the N-(2-hydroxyethyl) analog. It appears that the bulk and length of the moiety appended to arachidonic acid are more important determinants of affinity for CB1 than is hydrogen-bonding capability.
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