Theoretical conformational analysis of the opioid delta antagonist H-Tyr-Tic-Phe-OH and the mu agonist H-Tyr-D-Tic-Phe-NH2.
A molecular mechanics study (grid search and energy minimization) of the highly delta receptor-selective delta opioid antagonist H-Tyr-Tic-Phe-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 peptide bonds only and represent compact structures showing various patterns of aromatic ring stacking. The centrally located Tic residue imposes several conformational constraints on the N-terminal dipeptide segment; however, the results of molecular dynamics simulations indicated that this tripeptide still shows some structural flexibility, particularly at the Phe3 residue. Analogous studies performed with the structurally related mu receptor-selective mu agonist H-Tyr-D-Tic-Phe-NH2 resulted in low energy structures that were also compact but showed patterns of ring stacking different from those obtained with TIP. Superimposition of low energy conformers of TIP and H-Tyr-D-Tic-Phe-NH2 revealed that the Phe3 residues of the L-Tic- and the D-Tic peptide were always located on opposite sides of the plane defined by the Tic residue, thus providing an explanation for the distinct activity profiles of the two compounds in structural terms. Attempts to demonstrate spatial overlap between the pharmacophoric moieties of low energy conformers of TIP and the nonpeptide delta antagonist naltrindole were made by superimposing either the Tyr1 and Tic2 aromatic rings and the N-terminal amino group or the Tyr1 and Phe3 aromatic rings and the N-terminal amino group of the peptide with the corresponding aromatic rings and nitrogen atom in the alkaloid structure.(ABSTRACT TRUNCATED AT 250 WORDS)
Wilkes
B C
BC
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Quebec, Canada.
Schiller
P W
PW
D000595:Amino Acid Sequence; D007546:Isoquinolines / Q000737:chemistry*; D008969:Molecular Sequence Data; D009271:Naltrexone / Q000031:analogs & derivatives / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry*; D011487:Protein Conformation; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D044005:Tetrahydroisoquinolines; D013816:Thermodynamics
D007546:Isoquinolines; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; C083829:tyrosyl 1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanine; C078986:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D009271:Naltrexone; C055382:naltrindole