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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	13057-13074
Number of pages	18
Journal	Journal of Medicinal Chemistry
Volume	68
Issue number	12
DOIs	https://doi.org/10.1021/acs.jmedchem.5c01108
State	Published - Jun 26 2025

Bibliographical note

Publisher Copyright:
© 2025 American Chemical Society.

Funding

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.

Funders	Funder number
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

Access to Document

10.1021/acs.jmedchem.5c01108

Cite this

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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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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doi = "10.1021/acs.jmedchem.5c01108",

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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, no. 12, pp. 13057-13074. https://doi.org/10.1021/acs.jmedchem.5c01108

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

Access to Document

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Alpha2 Noradrenergic Antagonist as a Fentanyl Counter Measure

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

Alpha2 Noradrenergic Antagonist as a Fentanyl Counter Measure

Cite this