CONFORMATIONAL-ENERGY STUDIES OF TETRAPEPTIDE OPIATES - CANDIDATE ACTIVE AND INACTIVE CONFORMATIONS

  • 1 January 1982
    • journal article
    • research article
    • Vol. 22  (3) , 667-677
Abstract
The conformational behavior of 4 tetrapeptide enkephalin analogs (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 1st 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, or 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 2nd method of selection, conformers with relative energies in the active and inactive peptides that followed the potency order Tyr-Gly-Gly-Phe-OH .mchlt. Tyr-D-Ala-Gly-Phe-NH2 .ltoreq. 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 H bond, but instead was stabilized by a H bond between the Tyr amine H atom and the Phe carbonyl O2 atom. The effect of C-terminal amide derivatization on peptide conformation was 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-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. On the basis of conformational data, the Tyr-Gly-Gly-Phe-NH2 analog is predicted to have very weak opiate activity.