STRUCTURAL REQUIREMENTS FOR BINDING OF ANANDAMIDE-TYPE COMPOUNDS TO THE BRAIN CANNABINOID RECEPTOR

In order to establish the structural requirements for binding to the b rain cannabinoid receptor (CB1), we have synthesized numerous fatty ac id amides, ethanolamides, and some related simple derivatives and have determined their K-i values. A few alpha-methyl- or alpha,alpha-dimet hylarachidonoylalkylamides were also examined. In the 20:4, n-6 series , the unsubstituted amide is inactive; N-monoalkylation, at least up t o a branched pentyl group, leads to significant binding. N,N-Dialkylat ion, with or without hydroxylation on one of the alkyl groups, leads t o elimination of activity. Hydroxylation of the N-monoalkyl group at t he omega carbon atom retains activity. In the 20:x, n-6 series, x has to be either 3 or 4; the presence of only two double bonds leads to in activation. In the n-3 series, the limited data reported suggest that the derived ethanolamides are either inactive or less active than comp arable compounds in the n-6 series. Alkylation or dialkylation of the alpha carbon adjacent to the carbonyl group retains the level of bindi ng in the case of anandamide (compounds 48, 49); however, alpha-monome thylation or alpha,alpha-dimethylation of N-propyl derivatives (50-53) potentiates binding and leads to the most active compounds seen in th e present work (K-i values of 6.9 +/- 0.7 to 8.4 +/- 1.1 nM). We have confirmed that the presence of a chiral center on the N-alkyl substitu ent may lead to enantiomers which differ in their levels of binding (c ompounds 54, 57 and 55, 56).