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-NH2 (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 mu-receptor. Its conformational features have been studied using a combination, a 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 stabilized 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.