delta-Selective Opioid Peptides Containing a Single Aromatic Residue in the Message Domain: An NMR Conformational Analysis

The sequence of deltorphin I, a &selective opioid agonist. has been systematically modifled by inserting conformationally constrained C“.“ disubstituted apolar residues in the third position. As expected, substitution of Phe with AGC, Ac5c and Ac3c yields analogues with decreasing but sizeable affinity. Surprisbgly, substitution with Aib yields an analogue with almost the same binding affinity of the parent compound but with a greatly increased selectivity. This is the first case of a potent and very selective opioid peptide containing a single aromatic residue in the message domain. that is, only Qr’. Here we report a detailed conformational analysis of IAib31deltorphin I and [Ac6c3]deltorphinI in DMSO at room temperature and in a DMSOlwater cryomixture at low temperature, based on NMR spectroscopy and energy calculations. The peptides are highly structured in both solvents, as indicated by the exceptional fhdbg of a nearly zero temperature coefficient of Val5 NH resonance. NMR data cannot be explained on the basis of a single structure but it was possible to interpret all NMR data on the basis of a few structural families. The conformational averaging was analysed by means of an original computer program that yields qualitative and quantitative composition of the mixture. Comparison of the preferred solution conformations with two ngid &selective agonists shows that the shapes of [Aib3]deltorphin I and [Ac6c3]deltorphin I are consistent with those of rigid agonists and that the message domain of opioid peptides can be defhed only in conformational terms.