Cyclic Enkephalin Analogs with Exceptional Potency at Peripheral δ Opioid Receptors

A series of super potent and δ-opioid-receptor-selective cyclic hexapeptides of the general formula [formula omitted] (where X is hydrogen or halogen) has been synthesized. The unsubstituted hexapeptide [formula omitted] has extremely high potency at peripheral δ opioid receptors (IC₅₀ value in the MVD assay is 0.016 nM) and in bioassays is the most selective compound in this series. The introduction of halogens in the phenyl ring of phenylalanine at position 4 led to significant changes in the selectivity and affinities at peripheral and central opioid receptors. In the binding studies, the most potent compound is the p-fluoro analog, whereas the most selective analog is the p-iodo-substituted peptide.