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

Abstract

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. Based on 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 mixedefficacy 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 (Ki ~ 0.5 nM) to both receptors, but also showed kappa opioid receptor (KOR) agonist activity.

Molecular Docking of Opiates and Opioid Peptides, a Tool for the Design of Selective Agonists and Antagonists, and for the Investigation of Atypical Ligand-Receptor Interactions

“…This hypothesis was partially achieved with the cyclopeptide Tyr-c(S-CH 2 -S)[D-Cys-Phe-2-NalCys]NH 2 [94], that showed similar affinity for MOR and DOR but decreased DOR efficacy without compromising MOR agonism. This behavior was rationalized by docking the peptide in the modeled active and inactive conformations of MOR and DOR.…”

Modulation of Opioid Receptor Ligand Affinity and Efficacy Using Active and Inactive State Receptor Models

“…Our lab and others (6–18) have explored the development of mixed efficacy ligands where MOR agonist activity is combined with DOR antagonism in the same molecule using a “merged” pharmacophore (2). Such a multifunctional ligand would possess considerable advantages over the traditional approach of using a combination of selective opioid drugs with possibly differing pharmacokinetic or pharmacodynamic properties.…”

“…Since 1 has appreciable DOR efficacy, we then focused our efforts on designing ligands that retain MOR agonist activity, but with reduced DOR efficacy (6). Using our receptor models for both active and inactive states of MOR and DOR (6, 8, 20–24) we predicted that adding bulky aromatic substituents in the third or fourth position of peptide 1 would produce a steric clash in the DOR active state binding site which would not be seen in the DOR inactive site, thus favoring binding to the DOR inactive state and consequently resulting in lower DOR efficacy (6). Docking to corresponding active and inactive state MOR models revealed no analogous receptor state-specific adverse interactions; we therefore predicted that increasing steric bulk at position 3 or 4 would provide the desired MOR agonist/DOR antagonist profile.…”

The behavioral effects of a mixed efficacy antinociceptive peptide, VRP26, following chronic administration in mice

“…This is of particular interest in the field of opioid analgesics, as the co-administration of a mu opioid receptor (MOR) agonist with a delta opioid receptor (DOR) antagonist has been proposed to produce MOR-mediated analgesia with reduced tolerance and dependence liabilities (Abdelhamid et al 1991; Fundytus et al 1995; Hepburn et al 1997; Purington et al 2009; Schiller 2009a). The development of antinociceptive tolerance often leads to dose escalation which may contribute to the prevalence of opioid misuse and abuse (Ballantyne and LaForge 2007).…”