N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes as opioid receptors probes. 1. Investigation of the phenolic hydroxyl group

Riya R. Trivedi; Dan Luo; Marissa C. Hessing; Emily Prantzalos; Warren J. Alilain; Jill R. Turner; Thomas E. Prisinzano

doi:10.1016/j.ejmech.2025.117991

N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes as opioid receptors probes. 1. Investigation of the phenolic hydroxyl group

Riya R. Trivedi
, Dan Luo
, Marissa C. Hessing
, Emily Prantzalos
, Warren J. Alilain
, Jill R. Turner
, Thomas E. Prisinzano

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

Abstract

N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes represent a novel class of synthetic opioids with potent activity and a distinct pharmacological profile. The prototype of this class, atoxifent, exhibits strong opioid receptor activity while minimizing severe respiratory depression, distinguishing it from fentanyl. To gain deeper insight into ligand-receptor interactions and the factors influencing functional activity, we systematically investigated the role of the phenolic hydroxyl group. Our approach focused on (1) assessing hydrogen bonding interactions with opioid receptors, (2) modulating ionization via pKa adjustments, and (3) exploring bioisosteric replacements. In vitro assay showed that 3-amino (11), 3-cyclopropyl sulfonamide (12), and 3-carboxamido (13) derivatives retained high MOR agonist activity. Notably, 13 displayed approximately 2.4 times greater in vitro metabolic stability than atoxifent. In vivo antinociceptive studies showed that 11, 12, and 13 act as partial agonists. These findings offer valuable insight into how N-(3-hydroxyphenyl)-3,8-diazabicyclooctanes interact with opioid receptors.

Original language	English
Article number	117991
Journal	European Journal of Medicinal Chemistry
Volume	298
DOIs	https://doi.org/10.1016/j.ejmech.2025.117991
State	Published - Nov 15 2025

Bibliographical note

Publisher Copyright:
© 2025 Elsevier Masson SAS

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
National Center for Advancing Translational Sciences (NCATS)	UL1TR001998
National Institutes of Health (NIH)	P20 GM130456, S10 OD28690

Keywords

Antinociceptive activity
Functional selectivity
In vitro metabolism
MOR agonist

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

Access to Document

10.1016/j.ejmech.2025.117991

Cite this

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title = "N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes as opioid receptors probes. 1. Investigation of the phenolic hydroxyl group",

abstract = "N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes represent a novel class of synthetic opioids with potent activity and a distinct pharmacological profile. The prototype of this class, atoxifent, exhibits strong opioid receptor activity while minimizing severe respiratory depression, distinguishing it from fentanyl. To gain deeper insight into ligand-receptor interactions and the factors influencing functional activity, we systematically investigated the role of the phenolic hydroxyl group. Our approach focused on (1) assessing hydrogen bonding interactions with opioid receptors, (2) modulating ionization via pKa adjustments, and (3) exploring bioisosteric replacements. In vitro assay showed that 3-amino (11), 3-cyclopropyl sulfonamide (12), and 3-carboxamido (13) derivatives retained high MOR agonist activity. Notably, 13 displayed approximately 2.4 times greater in vitro metabolic stability than atoxifent. In vivo antinociceptive studies showed that 11, 12, and 13 act as partial agonists. These findings offer valuable insight into how N-(3-hydroxyphenyl)-3,8-diazabicyclooctanes interact with opioid receptors.",

keywords = "Antinociceptive activity, Functional selectivity, In vitro metabolism, MOR agonist",

author = "Trivedi, \{Riya R.\} and Dan Luo and Hessing, \{Marissa C.\} and Emily Prantzalos and Alilain, \{Warren J.\} and Turner, \{Jill R.\} and Prisinzano, \{Thomas E.\}",

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Masson SAS",

year = "2025",

month = nov,

day = "15",

doi = "10.1016/j.ejmech.2025.117991",

language = "English",

volume = "298",

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T1 - N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes as opioid receptors probes. 1. Investigation of the phenolic hydroxyl group

AU - Trivedi, Riya R.

AU - Luo, Dan

AU - Hessing, Marissa C.

AU - Prantzalos, Emily

AU - Alilain, Warren J.

AU - Turner, Jill R.

AU - Prisinzano, Thomas E.

PY - 2025/11/15

Y1 - 2025/11/15

N2 - N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes represent a novel class of synthetic opioids with potent activity and a distinct pharmacological profile. The prototype of this class, atoxifent, exhibits strong opioid receptor activity while minimizing severe respiratory depression, distinguishing it from fentanyl. To gain deeper insight into ligand-receptor interactions and the factors influencing functional activity, we systematically investigated the role of the phenolic hydroxyl group. Our approach focused on (1) assessing hydrogen bonding interactions with opioid receptors, (2) modulating ionization via pKa adjustments, and (3) exploring bioisosteric replacements. In vitro assay showed that 3-amino (11), 3-cyclopropyl sulfonamide (12), and 3-carboxamido (13) derivatives retained high MOR agonist activity. Notably, 13 displayed approximately 2.4 times greater in vitro metabolic stability than atoxifent. In vivo antinociceptive studies showed that 11, 12, and 13 act as partial agonists. These findings offer valuable insight into how N-(3-hydroxyphenyl)-3,8-diazabicyclooctanes interact with opioid receptors.

AB - N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes represent a novel class of synthetic opioids with potent activity and a distinct pharmacological profile. The prototype of this class, atoxifent, exhibits strong opioid receptor activity while minimizing severe respiratory depression, distinguishing it from fentanyl. To gain deeper insight into ligand-receptor interactions and the factors influencing functional activity, we systematically investigated the role of the phenolic hydroxyl group. Our approach focused on (1) assessing hydrogen bonding interactions with opioid receptors, (2) modulating ionization via pKa adjustments, and (3) exploring bioisosteric replacements. In vitro assay showed that 3-amino (11), 3-cyclopropyl sulfonamide (12), and 3-carboxamido (13) derivatives retained high MOR agonist activity. Notably, 13 displayed approximately 2.4 times greater in vitro metabolic stability than atoxifent. In vivo antinociceptive studies showed that 11, 12, and 13 act as partial agonists. These findings offer valuable insight into how N-(3-hydroxyphenyl)-3,8-diazabicyclooctanes interact with opioid receptors.

KW - Antinociceptive activity

KW - Functional selectivity

KW - In vitro metabolism

KW - MOR agonist

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ER -

N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes as opioid receptors probes. 1. Investigation of the phenolic hydroxyl group

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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Alpha2 Noradrenergic Antagonist as a Fentanyl Counter Measure

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N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes as opioid receptors probes. 1. Investigation of the phenolic hydroxyl group

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

Alpha2 Noradrenergic Antagonist as a Fentanyl Counter Measure

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