Searching for Synthetic Opioid Rescue Agents. 2: Identification of an Ultra-Potent Synthetic Opioid Rescue Agent

Jocelyn Martin; Edem Onyameh; Dan Luo; Joshua W. Powell; Riya R. Trivedi; Eric J. Woloshin; Yating Zhang; Jakob D. Shaykin; Emily D. Denehy; Alexia R. Alsum; Emily Prantzalos; Qianru Jiang; Tao Che; Warren J. Alilain; Jill R. Turner; Michael T. Bardo; Thomas E. Prisinzano

doi:10.1021/acs.jmedchem.5c01108

Searching for Synthetic Opioid Rescue Agents. 2: Identification of an Ultra-Potent Synthetic Opioid Rescue Agent

Jocelyn Martin, Edem Onyameh, Dan Luo, Joshua W. Powell, Riya R. Trivedi, Eric J. Woloshin, Yating Zhang, Jakob D. Shaykin, Emily D. Denehy, Alexia R. Alsum, Emily Prantzalos, Qianru Jiang, Tao Che, Warren J. Alilain, Jill R. Turner, Michael T. Bardo, Thomas E. Prisinzano

Producción científica: Article › revisión exhaustiva

Resumen

Ultrapotent synthetic opioids (UPSO) have become increasingly prevalent today, from being implicated in a mass casualty event to contaminating illicit drug supply across the country. These UPSOs are different than semisynthetic and naturally derived opioids, in the sense that UPSOs have a much greater ability to cause opioid-induced respiratory depression (OIRD) and wooden chest syndrome (WCS), two medical phenomena that are essential in the lethality of UPS opioids. Here, we report the identification of a potential rescue agent (9) that is more potent than naloxone (NLX) in vitro and fully reverses fentanyl- and carfentanil-induced ventilatory depression and fentanyl-induced vocal cord closure in rats. Unlike naloxone, rescue agent 9 increases minute ventilation above normal in fentanyl- or carfentanil-treated rats and appears to have limited brain penetrance. Targeting peripheral opioid receptors offers a new strategy for reversing OIRD, and 9 offers a lead toward developing such an agent.

Idioma original	English
Páginas (desde-hasta)	13057-13074
Número de páginas	18
Publicación	Journal of Medicinal Chemistry
Volumen	68
N.º	12
DOI	https://doi.org/10.1021/acs.jmedchem.5c01108
Estado	Published - jun 26 2025

Nota bibliográfica

Publisher Copyright:
© 2025 American Chemical Society.

Financiación

This work described was supported by the National Institute on Drug Abuse (U01 DA051377), National Center for Advancing Translational Sciences (UL1TR001998), the University of Kentucky Neuroscience Research Priority Area and Substance Use Research Priority Area, and the Kentucky Medical Services Foundation Endowed Chair in Pharmacy (T.E.P.). The authors thank the College of Pharmacy PharmNMR Center for analytical support. PharmNMR is supported in part by NIH grants S10 OD28690 and P20 GM130456. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Financiadores	Número del financiador
University of Kentucky Neuroscience
Author National Institute on Drug Abuse DA031791 Mark J Ferris National Institute on Drug Abuse DA006634 Mark J Ferris National Institute on Alcohol Abuse and Alcoholism AA026117 Mark J Ferris National Institute on Alcohol Abuse and Alcoholism AA028162 Elizabeth G Pitts National Institute of General Medical Sciences GM102773 Elizabeth G Pitts Peter McManus Charitable Trust Mark J Ferris National Institute on Drug Abuse	U01 DA051377
Author National Institute on Drug Abuse DA031791 Mark J Ferris National Institute on Drug Abuse DA006634 Mark J Ferris National Institute on Alcohol Abuse and Alcoholism AA026117 Mark J Ferris National Institute on Alcohol Abuse and Alcoholism AA028162 Elizabeth G Pitts National Institute of General Medical Sciences GM102773 Elizabeth G Pitts Peter McManus Charitable Trust Mark J Ferris National Institute on Drug Abuse
National Center for Advancing Translational Sciences (NCATS)	UL1TR001998
National Center for Advancing Translational Sciences (NCATS)
National Institutes of Health (NIH)	P20 GM130456, S10 OD28690
National Institutes of Health (NIH)

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Acceder al documento

10.1021/acs.jmedchem.5c01108

Otros archivos y enlaces

Alpha2 Noradrenergic Antagonist as a Fentanyl Counter Measure
Bardo, M. (PI), Prisinzano, T. (PI) & Alilain, W. (CoI)
University of Kentucky Neuroscience Research Priority Area
1/1/23 → 12/31/23
Proyecto: Research project

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Martin, J., Onyameh, E., Luo, D., Powell, J. W., Trivedi, R. R., Woloshin, E. J., Zhang, Y., Shaykin, J. D., Denehy, E. D., Alsum, A. R., Prantzalos, E., Jiang, Q., Che, T., Alilain, W. J., Turner, J. R., Bardo, M. T., & Prisinzano, T. E. (2025). Searching for Synthetic Opioid Rescue Agents. 2: Identification of an Ultra-Potent Synthetic Opioid Rescue Agent. Journal of Medicinal Chemistry, 68(12), 13057-13074. https://doi.org/10.1021/acs.jmedchem.5c01108

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title = "Searching for Synthetic Opioid Rescue Agents. 2: Identification of an Ultra-Potent Synthetic Opioid Rescue Agent",

abstract = "Ultrapotent synthetic opioids (UPSO) have become increasingly prevalent today, from being implicated in a mass casualty event to contaminating illicit drug supply across the country. These UPSOs are different than semisynthetic and naturally derived opioids, in the sense that UPSOs have a much greater ability to cause opioid-induced respiratory depression (OIRD) and wooden chest syndrome (WCS), two medical phenomena that are essential in the lethality of UPS opioids. Here, we report the identification of a potential rescue agent (9) that is more potent than naloxone (NLX) in vitro and fully reverses fentanyl- and carfentanil-induced ventilatory depression and fentanyl-induced vocal cord closure in rats. Unlike naloxone, rescue agent 9 increases minute ventilation above normal in fentanyl- or carfentanil-treated rats and appears to have limited brain penetrance. Targeting peripheral opioid receptors offers a new strategy for reversing OIRD, and 9 offers a lead toward developing such an agent.",

author = "Jocelyn Martin and Edem Onyameh and Dan Luo and Powell, \{Joshua W.\} and Trivedi, \{Riya R.\} and Woloshin, \{Eric J.\} and Yating Zhang and Shaykin, \{Jakob D.\} and Denehy, \{Emily D.\} and Alsum, \{Alexia R.\} and Emily Prantzalos and Qianru Jiang and Tao Che and Alilain, \{Warren J.\} and Turner, \{Jill R.\} and Bardo, \{Michael T.\} and Prisinzano, \{Thomas E.\}",

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Martin, J, Onyameh, E, Luo, D, Powell, JW, Trivedi, RR, Woloshin, EJ, Zhang, Y, Shaykin, JD, Denehy, ED, Alsum, AR, Prantzalos, E, Jiang, Q, Che, T, Alilain, WJ , Turner, JR , Bardo, MT & Prisinzano, TE 2025, 'Searching for Synthetic Opioid Rescue Agents. 2: Identification of an Ultra-Potent Synthetic Opioid Rescue Agent', Journal of Medicinal Chemistry, vol. 68, n.º 12, pp. 13057-13074. https://doi.org/10.1021/acs.jmedchem.5c01108

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AU - Prantzalos, Emily

AU - Jiang, Qianru

AU - Che, Tao

AU - Alilain, Warren J.

AU - Turner, Jill R.

AU - Bardo, Michael T.

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N2 - Ultrapotent synthetic opioids (UPSO) have become increasingly prevalent today, from being implicated in a mass casualty event to contaminating illicit drug supply across the country. These UPSOs are different than semisynthetic and naturally derived opioids, in the sense that UPSOs have a much greater ability to cause opioid-induced respiratory depression (OIRD) and wooden chest syndrome (WCS), two medical phenomena that are essential in the lethality of UPS opioids. Here, we report the identification of a potential rescue agent (9) that is more potent than naloxone (NLX) in vitro and fully reverses fentanyl- and carfentanil-induced ventilatory depression and fentanyl-induced vocal cord closure in rats. Unlike naloxone, rescue agent 9 increases minute ventilation above normal in fentanyl- or carfentanil-treated rats and appears to have limited brain penetrance. Targeting peripheral opioid receptors offers a new strategy for reversing OIRD, and 9 offers a lead toward developing such an agent.

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Searching for Synthetic Opioid Rescue Agents. 2: Identification of an Ultra-Potent Synthetic Opioid Rescue Agent

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

Acceder al documento

Otros archivos y enlaces

Huella

Proyectos

Alpha2 Noradrenergic Antagonist as a Fentanyl Counter Measure

Citar esto