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Comparative analysis of various proposed models of the receptor‐bound conformation of H‐tyr‐Tic‐Phe OH related δ‐opioid antagonists

1995; Wiley; Volume: 37; Issue: 6 Linguagem: Inglês

10.1002/bip.360370606

1097-0282

Brian C. Wilkes, Peter W. Schiller,

Receptor Mechanisms and Signaling

Abstract A molecular mechanics study (grid search and energy minimization) was performed with six δ opioid peptide antagonists containing a tetrahydroisoquinoline‐3‐carboxylic acid (Tic) residue in the 2‐position of the peptide sequence. Compounds examined were the highly potent and selective T1P(P) peptides H‐Tyr‐Tic‐Phe‐OH (TIP). H‐Tyr‐TicΨ[CH 2 ‐NH]Phe‐OH (TIP[Ψ]). H‐Tyr‐Tic‐Phe‐Phe‐OH (TIPP). and H‐Tyr‐TicΨ[CH 2 ‐NH]Phe‐Phe‐OH (TlPP[Ψ]), and the weakly active analogues H‐Tyr‐Tic‐NH 2 and H‐Tyr‐Tic‐Ala‐OH. Low energy conformers of the peptides were examined for their compatibility with three proposed model of the δ receptor‐bound conformation. Model 1, based on spatial overlap of the Tyr 1 and Phe 3 aromatic rings and N‐terminal amino group of the peptides with the corresponding aromatic rings and nitrogen atom of the nonpeptide δ‐antagonist naltrindole, was ruled out because of the demonstrated importance of the Tic 2 aromatic ring for δ antagonism and because of the somewhat elevated energies of the conformers consistent with this model. Models of the receptor‐bound conformation based on superimposition of the Tyr 1 and Tic 2 aromatic rings and N‐terminal amino group of the peptides with the corresponding moieties in naltrindole included an all‐trans peptide bond conformer [model 2, proposed by B. C. Wilkes and P. W. Schiller (1994) Biopolymers. Vol. 34. pp. 1213–1219] and a conformer with a cis peplide 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 consistent with both model 2 and model 3 were identified: however, peptide conformers corresponding to model 2 showed better coplanarity of the Tyr 1 aromatic ring and the phenol ring in naltrindole than peptide conformers corresponding to model 3. Both models remain plausible candidate structures for the receptor‐bound conformation of δ antagonists of the TIP(P) class. TIP(P) analogues containing additional conformational constraints need to be developed in order to arrive at a unique model. © 1994 John Wiley & Sons, Inc.