Pentapeptides Displaying μ Opioid Receptor Agonist and δ Opioid Receptor Partial Agonist/Antagonist Properties

Chronic use of mu-opioid agonists has been shown to cause neurochemical adaptations resulting in tolerance and dependence. While the analgesic effects of these drugs are mediated by mu-opioid receptors (MOR), several studies have shown that antagonism or knockdown of delta-opioid receptors (DOR) can lessen or prevent development of tolerance and dependence. On the basis of computational modeling of putative active and inactive conformations of MOR and DOR, we have synthesized a series of pentapeptides with the goal of developing a MOR agonist/DOR antagonist peptide with similar affinity at both receptors as a tool to probe functional opioid receptor interaction(s). The eight resulting naphthylalanine-substituted cyclic pentapeptides displayed variable mixed-efficacy profiles. The most promising peptide (9; Tyr-c(S-CH(2)-S)[D-Cys-Phe-2-Nal-Cys]NH(2)) displayed a MOR agonist and DOR partial agonist/antagonist profile and bound with equipotent affinity (K(i) approximately 0.5 nM) to both receptors, but also showed kappa opioid receptor (KOR) agonist activity.