Highly potent and selective zwitterionic agonists of the δ-opioid receptor. Part 1

A series of zwitterionic δ-opioid agonists, with targeted physicochemistry, as a strategy to limit potential for CNS exposure, were prepared. These agents were found to possess exquisite potency and selectivity over mu and κ-opiate activity. Furthermore, analogue 3a was found to display restricted CNS exposure, as evidenced by its inactivity in a rodent hyperlocomotion assay of central opiate activity. Dog pharmacokinetic studies on 3a indicated encouraging oral bioavailability.