Development of a model for the delta-opioid receptor pharmacophore. 4. Residue 3 dehydrophenylalanine analogues of Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) confirm required gauche orientation of aromatic side chain

Abstract

We have previously proposed a model for the delta-opioid receptor binding conformation of the high affinity tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) based on experimental and theoretical conformational analysis of this peptide and a correlation of conformational preferences of further conformationally restricted analogues of this tetrapeptide with their receptor binding affinities. A key element of this model is the requirement that the Phe3 side chain exist in the chi 1 = -60 degrees conformation. Conformational calculations on the residue 3 dehydrophenylalanine 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 cannot. These results lead to the prediction that the dehydro(Z)phenylalanine analogue should display similar delta-receptor binding affinity as JOM-13 while the dehydro(E)phenylalanine analogue is expected to bind less avidly. Synthesis and subsequent opioid receptor binding analysis of the dehydrophenylalanine analogues of JOM-13 confirm these predictions, lending support to the delta-pharmacophore model.