ENKEPHALIN ANALOGS AS SYSTEMICALLY ACTIVE ANTINOCICEPTIVE AGENTS - O-ALKYLATED AND N-ALKYLATED DERIVATIVES OF THE DIPEPTIDE AMIDE 6-DIMETHYLTYROSYL-N-(3-PHENYLPROPYL)-D-ALANINAMIDE

A number of O- and N-alkylated derivatives of the antinociceptive, ora lly active, mu-opioid-selective truncated enkephalin analog 6-dimethyl tyrosyl-N-(3-phenylpropyl)-D-alaninamide (2, SC-39566) were synthesize d to explore the structure-activity relationships of the series. The p arent molecule is quite forgiving of substitution on the tyrosyl pheno lic moiety and on the alanyl nitrogen. The tyrosyl and (phenylpropyl)a mide NH sites, however, appear to be critical to interactions with the receptor, for even modest changes at these sites cause great loss of binding potency.