CONFORMATIONAL RESTRICTION OF TYR AND PHE SIDE-CHAINS IN OPIOID-PEPTIDES - INFORMATION ABOUT PREFERRED AND BIOACTIVE SIDE-CHAIN TOPOLOGY

The side chain of Tyr and Phe was fixed into the gauche (-) or gauche (+) conformation by using the Tic or Htc structures, and into the tran s conformation by using an aminobenzazepine-type (Aba) structure. When incorporated into dermorphin or deltorphin II, the Tic and Htc analog ues ail showed a large decrease in both mu and delta affinities and ac tivities. Fixation of Phe(3) in the trans rotamer resulted in a large increase in delta affinity in the dermorphin analogue, whereas in the [Aba(3)-Gly(4)] deltorphin II analogue, good delta affinity is maintai ned despite the removal of the Gh side chain. Whereas several authors propose a gauche (-) preferred conformation for the Phe(3) side chain, these results suggest a trans conformation at the 6 receptor The use of these conformationally constrained residues for evaluating the pref erred solution conformation in the flexible N-terminal tripeptide Tyr- D-Ala-Phe is illustrated The H-1-nmr parameters - chemical shift, temp erature dependence, and nuclear Overhauser effects to the D-Ala(2) met hyl protons in the different analogues - provide direct evidence to co nfirm the proposed sandwich conformation in the native peptides. (C) 1 996 John Wiley & Sons, Inc.