CYCLIC ENKEPHALIN ANALOGS WITH EXCEPTIONAL POTENCY AT PERIPHERAL DELTA-OPIOID RECEPTORS

A series of super potent and delta-opioid-receptor-selective cyclic he xapeptides of the general formula H-Tyr-D-Pen-Gly-Phe(p-X)-Cys-Phe-OH (where X is hydrogen or halogen) has been synthesized. The unsubstitut ed hexapeptide H-Tyr-D-Pen-Gly-Phe-Cys-Phe-OH (HB-P2, [Phe(6)]DPLCE) h as extremely high potency at peripheral delta opioid receptors (IC50 v alue in the MVD assay is 0.016 nM) and in bioassays is the most select ive compound in this series, The introduction of halogens in the pheny l ring of phenylalanine at position 4 led to significant changes in th e selectivity and affinities at peripheral and central opioid receptor s. In the binding studies, the most potent compound is the p-fluoro an alog, whereas the most selective analog is the p-iodo-substituted pept ide.