Characterization of a Nonselective Opioid Receptor Functional Antagonist: Implications for Development as a Novel Opioid Dependence Medication

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 dep...

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Veröffentlicht in:ACS pharmacology & translational science 2024-03, Vol.7 (3), p.654-666
Hauptverfasser: Shahbazi Nia, Siavash, Ortiz, Yuma T., Zuarth Gonzalez, Julio D., Shamir, Leila, Frimpong-Manson, Kofi, Hossain, Mohammad Anwar, Shahi, Sadisna, Bandy, Rayna, Bhat, Anoushka, Patel, Dhavalkumar, Diab, Hanin, Thompson, Jonathan, McMahon, Lance R., Wilkerson, Jenny L., German, Nadezhda A.
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container_end_page 666
container_issue 3
container_start_page 654
container_title ACS pharmacology & translational science
container_volume 7
creator Shahbazi Nia, Siavash
Ortiz, Yuma T.
Zuarth Gonzalez, Julio D.
Shamir, Leila
Frimpong-Manson, Kofi
Hossain, Mohammad Anwar
Shahi, Sadisna
Bandy, Rayna
Bhat, Anoushka
Patel, Dhavalkumar
Diab, Hanin
Thompson, Jonathan
McMahon, Lance R.
Wilkerson, Jenny L.
German, Nadezhda A.
description 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.
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title Characterization of a Nonselective Opioid Receptor Functional Antagonist: Implications for Development as a Novel Opioid Dependence Medication
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