POTENT MORPHICEPTIN ANALOGS - STRUCTURE ACTIVITY RELATIONSHIPS AND MORPHINE-LIKE ACTIVITIES

Abstract

Morphiceptin (Tyr-Pro-Phe-Pro-NH2), a nonenkephalin peptide, is an opioid agonist highly selective for .mu. opiate receptors. Chemical modification of morphiceptin was carried out by substituting structurally related amino acids at residues 2, 3 and 4. The morphiceptin analogs synthesized were then examined for receptor binding activities using 125I-labeled FK 33,824 [(2-D-alanine, 4-N-methylphenylalanine, 5-methional sulfoxide) enkephalin] as the .mu.-ligand and 125I-labeled D-Ala2,D-Leu5-enkephalin as the .delta.-ligand, and for inhibitory activities on electrically evoked smooth muscle contraction of mouse vas deferens and isolated myenteric plexus-longitudinal muscle strips of guinea pig ileum. All of these analogs showed virtually no activity at .delta. opiate receptor binding sites. Methylation of the N atom of Phe-and the substitution at the C-terminal of L-Pro by D-Pro produced potent .mu.-agonists, the prototype analog being Tyr-Pro-NMePhe-D-Pro-NH2 (PL017). The IC50 [median inhibitory concentration] values of morphiceptin and its analogs for .mu. receptor binding were correlated to the ED50 values in the guinea-pig ileum assay, suggesting that the ileum effects were mediated by .mu. receptor interactions. A similar correlation between .mu. receptor binding activity and the ED50 values in the mouse vas deferens assay suggested that morphiceptin and its analogs also acted on .mu. receptors in this tissue. This idea is supported by the observation that naloxone has a high pA2 [competitive antagonistic activity] value of 8.71 against PL017 in mouse vas deferens. In in vivo studies, PLO17 administered centrally into the rostral portion of the 4th ventricle produced long-lasting, naloxone-reversible analgesia in rats. The analgesic activity of PL017 is comparable to that reported for other potent enkephalin analogs. PL017, infused centrally in rats with osmotic minipumps, produced physical dependence. Chemical modification of peptides not related to the enkephalins can result in compounds with powerful morphine-like properties.