X‐Ray structure of Tyr‐D‐Tic‐Phe‐Phe‐NH₂ (D‐TIPP‐NH₂), a highly potent μ‐receptor selective opioid agonist. Comparisons with proposed model structures

Tyr‐D‐Tic‐Phe‐Phe‐NH 2 (D‐TIPP), a linear tetrapeptide containing the conformationally restricted Tic residue (tetrahydroisoquinoline‐3‐carboxylic acid), is an opioid agonist which exhibits high affinity and selectivity for the μ‐receptor. Its conformational features have been studied using a combination of solid‐state (X‐ray) and modeling (molecular mechanics and Monte Carlo simulations) methods. The results of the X‐ray study showed two distinct conformers for D‐TIPP, with the main differences lying in the orientation of the Tyr side‐chain and the presence of both D‐Tic(+) and D‐Tic(—) conformations for the D‐Tic residue. The peptide backbone is folded and stablized by the formation of one intramolecular hydrogen bond. The modeling results also indicated a folded backbone for the peptide and both cis and trans conformers for the D‐Tic residue are found in the lowest‐energy structures. Comparison of the X‐ray and modeling results shows many similarities especially around the D‐Tic residue. © Munksgaard 1997.