Cyclic and acyclic partial retro-inverso enkephalinamides: Mu receptor selective enzyme resistant analogs

The cyclic partial retro-inverso modified enkephalins, H-Tyr-cyclo[-D-Glu-Gly-gPhe-D-Leu-] (I), H-Tyr-cyclo[-D-A2bu-Gly-gPhe-R&S-mLeu-] (IIf, IIs), H-Tyr-cyclo[-D-Glu-Gly-Phe-gLeu-] (III), and their corresponding acyclic analogs, H-Tyr-D-Ala-Gly-gPhe-D-Leu-For (Ia), H-Tyr-D-Ala-Gly-gPhe-R,S-mLeu-NH2 (IIa), H-Tyr-D-Ala-Gly-Phe-gLeu-For (IIIa) have been evaluated in in vitro bioassays. Relative to Leu-enkephalin, the modified compounds are more potent in the guinea pig ileum assay and more effectively displace [3H]naloxone from rat brain receptors, while they are generally less potent in the mouse vas deferens assay and only weakly able to displace [3H] (D-Ala2, D-Leu5)enkephalin. The analogs are highly resistant to proteolytic degradation by rat brain membrane preparations that readily hydrolyze Leu-enkephalin.