Pharmacological Characterization of Novel Opioid Receptor Ligands Aimed at Reducing the Development of Tolerance

Abstract

The three opioid receptor subtypes, mu (µ), delta (δ) and kappa (κ) have long been associated with analgesia. Traditional opioid analgesics exert their effects through µ receptors located in the CNS. Recent studies suggest that the development of opioid analgesics displaying dual properties of µ agonism and δ antagonism could be of benefit by retaining potent analgesic properties while reducing the development of tolerance with chronic administration. UMB 425 displays high affinity at the µ receptor (K i = 3.2 ± 0.14 nM), moderate affinity at the δ and κ receptor In vitro [ 35 S]GTPγS functional assay results indicate that UMB 425 acts as partial agonist at the µ receptor, whilst having competitive antagonistic properties at the δ receptor. UMB 425 displays potent acute analgesic activity in vivo for both the hot plate and tail-flick assays, comparable to morphine itself. To ensure proper opioid-induced mechanisms pretreatment studies were performed using naloxone, a non-selective opioid antagonist, and nor-BNI, a selective κ-antagonist. Naloxone attenuates the analgesic effects induced by an acute ED 90 of UMB 425, while nor-BNI shows no significant reduction. A chronic dosing paradigm was designed to determine UMB 425 induced analgesic tolerance. UMB 425 maintains significantly higher levels of analgesia compared to morphine on the fifth day of this chronic dosing paradigm. A dose-response challenge performed on the sixth day of this paradigm indicates a smaller shift in respective ED 50 values for UMB 425 as compared to morphine for both the tail-flick (1.3-/6.4-fold) and hot plate (3.0-/7.8-fold) assays, effectively demonstrating reduced analgesic tolerance liabilities for UMB 425.