THEORETICAL CONFORMATIONAL-ANALYSIS OF THE OPIOID DELTA-ANTAGONIST H-TYR-TIC-PHE-OH AND THE MU-AGONIST H-TYR-D-TIC-PHE-NH2

Citation
Bc. Wilkes et Pw. Schiller, THEORETICAL CONFORMATIONAL-ANALYSIS OF THE OPIOID DELTA-ANTAGONIST H-TYR-TIC-PHE-OH AND THE MU-AGONIST H-TYR-D-TIC-PHE-NH2, Biopolymers, 34(9), 1994, pp. 1213-1219
Citations number
12
Categorie Soggetti
Biology
Journal title
ISSN journal
00063525
Volume
34
Issue
9
Year of publication
1994
Pages
1213 - 1219
Database
ISI
SICI code
0006-3525(1994)34:9<1213:TCOTOD>2.0.ZU;2-K
Abstract
A molecular mechanics study (grid search and energy minimization) of t he highly delta receptor-selective delta opioid antagonist H-Tyr-Tic-P he-OH (TIP; Tic: tetrahydroisoquinoline-3-carboxylic acid) resulted in four low energy conformers with energies within 2 kcal/mol of that of the lowest energy structure. These four conformers contain trans pept ide bonds only and represent compact structures showing various patter ns of aromatic ring stacking. The centrally located Tic residue impose s several conformational constraints on the N-terminal dipeptide segme nt; however, the results of molecular dynamics simulations indicated t hat this tripeptide still shows some structural flexibility, particula rly at the Phe(3) residue. Analogous studies performed with the struct urally related mu receptor-selective mu agonist H-Tyr-D-Tic-Phe-NH2 re sulted in low energy structures that were also compact but showed patt erns of ring stacking different from those obtained with TIP. Superimp osition of low energy conformers of TIP and H-Tyr-D-Tic-Phe-NH2 reveal ed that the Phe(3) residues of the L-Tic- and the D-Tic peptide were a lways located on opposite sides of the plane defined by the Tic residu e, thus providing an explanation for the distinct activity profiles of the two compounds in structural terms. Attempts to demonstrate spatia l overlap between the pharmacophoric moieties of low energy conformers of TIP and the nonpeptide delta antagonist naltrindole were made by s uperimposing either the Tyr(1) and Tic(2) aromatic rings and the N-ter minal amino group or the Tyr(1) and Phe(3) aromatic rings and the N-te rminal amino group of the peptide with the corresponding aromatic ring s and nitrogen atom in the alkaloid structure. In each case a low ener gy structure of TIP was found that showed good spatial overlap of all three specified pharmacophoric groups. These two conformers may repres ent candidate structures for the delta receptor-bound conformation of TIP. (C) 1994 John Wiley & Sons, Inc.