COMPARATIVE-ANALYSIS OF VARIOUS PROPOSED MODELS OF THE RECEPTOR-BOUNDCONFORMATION OF H-TYR-TIC-PHE-OH RELATED DELTA-OPIOID ANTAGONISTS

A molecular mechanics study (grid search and energy minimization) was performed with six delta opioid peptide antagonists containing a tetra hydroisoquinoline-3-carboxylic acid(Tic) residue in the 2-position of the peptide sequence. Compounds examined were the highly potent and se lective TIP(P) peptides H-Tyr-Tic-Phe-OH (TIP), H-Tyr-Tic Psi[CH2-NH] Phe-OH (TIP[Psi]), H-Tyr-Tic-Phe-Phe-OH (TIPP), and H-Tyr-Tic Psi[CH2- NH] Phe-Phe-OH (TIPP[Psi]), and the weakly, active analogues H-Tyr-Tic -NH2 and H-Tyr-Tic-Aln-OH. Low energy conformers of the peptides were examined for their compatibility with three proposed models of the 6 r eceptor-bound conformation Model 1, based on spatial overlap of the Ty r(1) and Phe(3) aromatic rings and N-terminal amino group of the pepti des with the corresponding aromatic rings and nitrogen atom of the non peptide delta-antagonist naltrindole, was ruled out because of the dem onstrated importance of the Tic(2) aromatic ring for delta antagonism and because of the somewhat elevated energies of the conformers consis tent with this model. Models of the receptor bound conformation based on superimposition of the Tyr(1) and Tic(2) aromatic rings and N-termi nal amino group of the peptides with the corresponding moieties in nal trindole inducted an all-trans peptide bond conformer [model 2, propos ed by B. C. Wilkes and P. W. Schiller (1994) Biopolymers, Vol. 34, pp. 1213-1219] and a conformer with a cis peptide bond between the Tyr(1) and Tic(2) residues (model 3, originally proposed by P. A. Temussi et al. [(1994) Biochemical and Biophysical Research Communications, Vol. 198, pp. 933-939]. For all six peptides low energy conformers consist ent with both model 2 and model 3 were identified, however, peptide co nformers corresponding to model 2 showed better coplanarity of the Tyr (1) aromatic ring and the phenol ring in naltrindole than peptide conf ormers corresponding to model 3. Both models remain plausible candidat e structures for the receptor bound conformation of delta antagonists of the TIP(P) class. TIP(P) analogues containing additional conformati onal constraints need to be developed in order to arrive at a unique m odel. (C) 1995 John Wiley & Sons, Inc.