Dihydromorphine-peptide hybrids have mu receptor antagonistic and delta receptor agonistic activity on the mouse vas deferens and bind with high affinity to opioid receptors in rat brain.

The actions of three morphine derivatives with short peptide side chains were evaluated upon the contraction of the isolated, electrically stimulated mouse vas deferens preparation and upon displacement of specifically bound 3H-etorphine in rat brain membranes. NIH-9834 (N-[6, 14-endoetheno-7, 8-dihydromorphine-7-alpha-carbonyl]-L-phenylalanyl-L-leucinol) and its ethyl ester, NIH-9833, were potent agonists upon the vas deferens. ICI-174864, 100 nM, markedly antagonized the actions of both NIH-9833 and NIH-9834 which indicates that these are delta receptor agonists. NIH-9835 (N-[6, 14-endoetheno-7, 8-dihydromorphine-7-alpha-carbonyl]-L-glycyl-L-phenylalanyl-L-leucine ethyl ester HCl) differs from NIH-9833 and NIH-9834 by the presence of a single amino acid residue. Although this drug had no agonistic activity on the vas deferens, it was a potent antagonist of mu agonists. All three hybrids were potent displacers of 3H-etorphine in rat cerebral membranes. The observation that addition of a single glycyl residue changes dihydromorphine-peptide analogs from potent delta receptor agonists to equally potent mu receptor antagonists suggests that the two receptor sites might be structurally quite similar.