Abstract
Opioid use, abuse and addiction have risen dramatically over the past few years. Opioid antagonists are used to manage acute opioid withdrawal, addiction, and peripheral side effects of opioid therapy. We have developed reversible and selective mu opioid neutral antagonists to aid in opioid overdose therapy while potentially minimizing withdrawal as compared to inverse agonists. We characterized two novel 6β‐N‐heterocyclic naltrexamine derivatives (NAP and NAQ) in mouse models of opioid‐mediated antinociception, locomotor activity, gastrointestinal transit, physical dependence and acetic acid writhing and also in an in vitro beta‐arrestin2‐GFP translocation assay. NAQ produced dose‐and time‐dependent reversal of morphine‐induced antinociception and hyperlocomotion and suppressed writhing behavior after acetic acid administration. In chronic morphine treated mice, NAQ produced modest withdrawal at higher doses that was much lower in intensity compared to equivalent doses of naloxone. NAP and NAQ antagonized DAMGO induced beta‐arrestin2 recruitment in MOR expressing cells. NAP also had a different pharmacokinetic profile, having a longer time to reach peak effect and a longer duration of action. NAP and NAQ demonstrate a unique pharmacology and may represent new and improved therapies for managing opioid overdose, addiction, and side effects associated with opioid analgesics.
Published Version
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