CANNABINOID RECEPTOR-BINDING AND AGONIST ACTIVITY OF AMIDES AND ESTERS OF ARACHIDONIC-ACID

The cannabinoid receptor in brain (CB1) specifically binds Delta(9)-te trahydrocannabinol, the predominant central nervous system-active comp onent of marijuana. An eicosanoid found in brain, N-(2-hydroxyethyl)ar achidonylamide (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 inact ivation of esterases/amidases. Arachidonyl esters were 30-fold less po tent than N-(2-hydroxyethyl)arachidonylamide, showing a rank order of potency of methyl = ethyl > propyl = isopropyl, Within the N-(hydroxya lkyl)arachidonylamide series, a one-carbon increase in chain length in creased the potency e-fold, but continued extension decreased affinity . Substituting the amide for the N-(2-hydroxyethylamide function produ ced a 4-fold loss of affinity. The N-(propyl)-, N-(butyl)-, and N-(Ben zyl)arachidonylamide derivatives exhibited a 3-fold increase, no chang e, and a 5-fold decrease, respectively, in affinity, Compared with N-( 2-hydroxyethyl)arachidonylamide. Both the methoxy ether and the formam ide derivatives suffered > 20-fold loss of potency, compared with N-(2 -hydroxyethyl)arachidonylamide. N-(2-Aminoethyl)arachidonylamide inter acted poorly with CB1. At 100 mu M, N-(2-hydroxyethyl)amide analogs of prostaglandin E(2), A(2), B-2, and B-1 failed to alter [H-3]CP55940 b inding to CB1. N-(2-Hydroxyethyl)arachidonylamide inhibited adenylate cyclase with lesser potency but with similar efficacy, compared with d esacetyllevon-antradol. Extending the length of the hydroxyalkyl moiet y by one carbon increased the apparent potency by 1 order of magnitude . The N-(propyl) derivative exhibited a 5-fold greater potency than di d the N-(2-hydroxyethyl) analog. It appears that the bulk and length o f the moiety appended to arachidonic acid are more important determina nts of affinity for CB1 than is hydrogen-bonding capability.