posted on 2024-02-12, 18:36authored bySiavash Shahbazi Nia, Yuma T. Ortiz, Julio D. Zuarth Gonzalez, Leila Shamir, Kofi Frimpong-Manson, Mohammad Anwar Hossain, Sadisna Shahi, Rayna Bandy, Anoushka Bhat, Dhavalkumar Patel, Hanin Diab, Jonathan Thompson, Lance R. McMahon, Jenny L. Wilkerson, Nadezhda A. German
Opioids
represent the most extensive category of abused substances
in the United States, and the number of fatalities caused by these
drugs exceeds those associated with all other drug overdoses combined.
The administration of naltrexone, a potent pan-opioid receptor antagonist,
to an individual dependent on opioids can trigger opioid withdrawal
and induce severe side effects. There is a pressing demand for opioid
antagonists free of opioid withdrawal effects. In our laboratory,
we have identified a compound with affinity to mu, delta, and kappa
opioid receptors in the range of 150–250 nM. This blood–brain
barrier (BBB)-permeant compound was metabolically stable in
vitro and in vivo. Our in vivo work demonstrated that 1–10 mg/kg intraperitoneal administration
of our compound produces moderate efficacy in antagonizing morphine-induced
antiallodynia effects in the chemotherapy-induced peripheral neuropathy
(CIPN) model. The treatment was well-tolerated and did not cause behavioral
changes. We have observed a fast elimination rate of this metabolically
stable molecule. Furthermore, no organ toxicity was observed during
the chronic administration of the compound over a 14-day period. Overall,
we report a novel functional opioid antagonist holds promise for developing
an opioid withdrawal therapeutic.