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
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.