Redoubling the Ring Size of an Endomorphin-2 Analog Transforms a Centrally Acting Mu-Opioid Receptor Agonist into a Pure Peripheral Analgesic

The study reports the synthesis and biological evaluation of two opioid analogs, a monomer and a dimer, obtained as products of the solid-phase, side-chain to side-chain cyclization of the pentapeptide Tyr-D-Lys-Phe-Phe-AspNH(2). The binding affinities to the mu, delta, and kappa opioid receptors, as well as results obtained in a calcium mobilization functional assay are reported. Tyr[D-Lys-Phe-Phe-Asp](2)-NH2 1 was a potent and selective full agonist of mu with sub-nanomolar affinity, while the dimer ( Tyr-[D-Lys-Phe-Phe-Asp](2)-NH2)(2) 2 showed a significant mixed mu/ kappa affinity, acting as an agonist at the mu. Molecular docking computations were utilized to explain the ability of the dimeric cyclopeptide 2 to interact with the receptor. Interestingly, in spite of the increased ring size, the higher flexibility allowed 2 to fold and fit into the mu receptor binding pocket. Both cyclo-peptides were shown to elicit strong antinociceptive activity after intraventricular injection but only cyclomonomer 1 was able to cross the blood-brain barrier. However, the cyclodimer 2 displayed a potent peripheral antinociceptive activity in a mouse model of visceral inflammatory pain. (C) 2016 Wiley Periodicals, Inc