Conformational-energy studies of tetrapeptide opiates. Candidate active and inactive conformations

G Loew, G Hashimoto, L Williamson, S Burt and W Anderson

The conformational behavior of four tetrapeptide enkephalin analogues (Tyr-Gly-Gly-Phe-OH, Tyr-Gly-Gly-Phe-NH2, Tyr-D-Ala-Gly-Phe-NH2, and Tyr-D-Ala-Gly-(NMe)Phe-NH2) was examined to identify conformations that are active and inactive at the opiate analgesic receptor. By using an empirical energy program, conformational energies were obtained for the optimized geometries of each tetrapeptide. Two methods of selecting candidate active conformations from low-energy conformers were used. In the first method, inactive conformers were designated as low-energy conformations of the very weak tetrapeptide, Tyr-Gly-Gly-Phe-OH. These candidate inactive conformers had geometries resembling beta V, beta I, "random" peptide conformations. Candidate active conformers selected were low-energy conformations found for both Tyr-D-Ala-Gly-Phe-NH2 and Tyr-D-Ala-Gly-(NMe)Phe-NH2 but not low-energy conformers for Tyr-Gly- Gly-Phe-OH. In the second method of selection, conformers with relative energies in the active and inactive peptides that followed the potency order Tyr-Gly-Gly-Phe-OH much less than Tyr-D-Ala-Gly-Phe-NH2 less than or equal to Tyr-D-Ala-Gly-(NMe)Phe-NH2 were chosen as candidate active conformers. By using both methods of selection, a beta II' bend geometry was found as the active conformer. This beta II' conformer was not stabilized by a 1-4 hydrogen bond, but instead was stabilized by a hydrogen bond between the tyrosine amine hydrogen atom and the phenylalanine carbonyl oxygen atom. The effect of C-terminal amide derivitization on peptide conformation was also examined by comparing the conformational profiles of Tyr-Gly-Gly-Phe-OH and Tyr-D-Ala-Gly-Phe- OH with their amides Tyr-Gly-Gly-Phe-OH-NH2 and Tyr-D-Ala-Gly-Phe-NH2. No significant difference in conformational behavior was found for the Tyr-Gly-Gly-Phe pair; however, a difference in conformational behavior was found between the Tyr-D-Ala-Gly-Phe acid and amide. Thus, on the basis of conformational data, the Tyr-Gly-Gly-Phe-NH2 analogue is predicted to have very weak opiate activity.

Volume 22, Issue 3, pp. 667-677, 11/01/1982
Copyright © 1982 by American Society for Pharmacology and Experimental Therapeutics