DEVELOPMENT OF A MODEL FOR THE DELTA-OPIOID RECEPTOR PHARMACOPHORE .4. RESIDUE-3 DEHYDROPHENYLALANINE ANALOGS OF TYR-C[D-CYS-PHE-D-PEN]OH(JOM-13) CONFIRM REQUIRED GAUCHE ORIENTATION OF AROMATIC SIDE-CHAIN

We have previously proposed a model for the delta-opioid receptor bind ing conformation of the high affinity tetrapeptide Tyr-c[D-Cys-Phe-D-P en] OH (JOM-13) based on experimental and theoretical conformational a nalysis of this peptide and a correlation of conformational preference s of further conformationally restricted analogous of this tetrapeptid e with their receptor binding affinities. A key element of this model is the requirement that the Phe(3) side chain exist in the chi(1) = -6 0 degrees conformation. Conformational calculations on the residue 3 d ehydrophenylalanine analogues of JOM-13 suggest that while the dehydro (Z)phenylalanine analogue can be superimposed easily with the proposed binding conformer of JOM-13, the dehydro(E)phenylalanine analogue can not. These results lead to the prediction that the dehydro(Z)phenylala nine analogue should display similar delta-receptor binding affinity a s JOM-13 while the dehydro(E)phenylalanine analogue is expected to bin d less avidly. Synthesis and subsequent opioid receptor binding analys is of the dehydrophenylalanine analogues of JOM-13 confirm these predi ctions, lending support to the delta-pharmacophore model. (C) 1996 Joh n Wiley & Sons, Inc.