Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent

Autor:	Mary Jeanne Kreek, Dan Luo, Markos Leggas, Sidnee L. Hedrick, Karen S. Jackson, Thomas E. Prisinzano, Sophia Kaska, Jamie Horn, Kumar Kulldeep Niloy, Caroline Baynard, Eduardo R. Butelman, Rupam Sarma
Rok vydání:	2021
Předmět:	Agonist Male medicine.drug_class Endocrinology Diabetes and Metabolism Narcotic Antagonists Clinical Biochemistry Structure–activity relationship (+)-Naloxone Pharmacology Naltrexone Fentanyl MOR antagonist Mice Opioid receptor Medicine Animals Pharmacology (medical) Molecular Biology business.industry Antinociceptive activity Research Biochemistry (medical) Antagonist Cell Biology General Medicine Analgesics Opioid Mice Inbred C57BL Opioid Drug Design business Oxycodone medicine.drug
Zdroj:	Journal of Biomedical Science Journal of Biomedical Science, Vol 28, Iss 1, Pp 1-18 (2021)
ISSN:	1423-0127
Popis:	Background One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids. Methods A series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay. Results A series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 = 2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of ~ 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01–0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488. Conclusions Methods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2590cb297de3149e84af545a518a8be5 https://pubmed.ncbi.nlm.nih.gov/34503531 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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