THE RECEPTOR-BOUND CONFORMATION OF H-TYR-TIC-(PHE-PHE)-OH-RELATED DELTA-OPIOID ANTAGONISTS CONTAINS ALL-TRANS PEPTIDE-BONDS

Two different models for the receptor-bound conformation of delta-opio id peptide antagonists containing the N-terminal dipeptide segment H-T yr-Tic (Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxy acid) have been proposed. Both models are based on spatial overlap of the Tyr(1) and Tic(2) aromatic rings and N-terminal amino group with the correspondin g aromatic rings and nitrogen atom of the nonpeptide delta-antagonist naltrindole. However, in one model the peptide bond between the Tyr(1) and Tic(2) residues assumes the trans conformation, whereas in the ot her it is in the cis conformation. To distinguish between these two mo dels, we prepared the two peptides H-Tyr psi[CH2NH]Tic-Phe-Phe-OH and H-Tyr psi[CH2NH]MeTic-Phe-Phe-OH (MeTic = 3-methyl-1,2,3,4-tetrahydroi soquinoline-3-carboxy acid) in which a cis peptide bond between the Ty r and Tic (or MeTic) residues is sterically forbidden. Both compounds turned out to be moderately potent delta-opioid antagonists in the mou se vas deferens assay. A molecular mechanics study performed with both peptides resulted in low-energy conformations in which the torsional angle (''omega(1)'') of the reduced peptide bond between Tyr and Tic ( or MeTic) had a value of 180 degrees (trans conformation) and which we re in good agreement with the proposed model with all trans peptide bo nds. Furthermore, this study confirmed that neither of these two pepti des could assume low-energy conformations in which ''omega(1)'' had a value of 0 degrees (cis conformation). Conformers with that same bond in the gauche conformation (''omega(1)'' = -60 degrees) were also iden tified, but were higher in energy and showed no spatial overlap with n altrindole. On the basis of these results it is concluded that the rec eptor-bound conformation of delta-peptide antagonists containing an N- terminal H-Tyr-Tic-dipeptide segment must have all trans peptide bonds . (C) Munksgaard 1998.