Synthesis and evaluation of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydromorphinone derivatives: mixed partial agonists at mu opioid and nociception/orphanin FQ peptide receptors

Mehrnoosh Ostovar; Keith Olsen; Gerta Cami-Kobeci; John R. Traynor; Luka Jeramaz; Stewart B. Kirton; Stephen M. Husbands

doi:10.1039/d5md00685f

Synthesis and evaluation of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydromorphinone derivatives: mixed partial agonists at mu opioid and nociception/orphanin FQ peptide receptors

Mehrnoosh Ostovar, Keith Olsen, Gerta Cami-Kobeci, John R. Traynor, Luka Jeramaz, Stewart B. Kirton, Stephen M. Husbands

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

Abstract

Opioids remain the standard of care for management of severe pain, but adverse effects limit their use, particularly for the treatment of chronic pain. Compounds that have dual partial agonist activity at mu opioid (MOP) and nociceptin opioid peptide (NOP) receptors have been shown, in non-human primates, to display excellent analgesic activity with greatly reduced adverse effect profile. In this study we looked to increase the range of MOP/NOP dual acting compounds and, in particular, provide ligands with a greater diversity of MOP:NOP profiles. Reduction of the C₆ carbonyl in the naltrexone scaffold to methylene resulted in a balanced MOP:NOP receptor profile in this series, in particular increasing potency at the NOP receptor. Ultimately, this will allow us to determine the optimal profiles for a range of therapeutic indications including pain and drug use disorders.

Original language	English
Pages (from-to)	1950-1960
Journal	RSC Medicinal Chemistry
Volume	17
Issue number	4
Early online date	12 Feb 2026
DOIs	https://doi.org/10.1039/d5md00685f
Publication status	Published - 1 Apr 2026

Data Availability Statement

Chemical characterisation data supporting this article have been uploaded as part of the supplementary information (SI).

Supplementary information: 1H and 13C NMR spectra and image from docking of 11e to MOP. See DOI: https://doi.org/10.1039/d5md00685f

Funding

CHO-hDOPr were a generous gift from L. Toll; the hMOPr and hKOPr cells were a generous gift from J. Streicher. The authors gratefully acknowledge the Material and Chemical Characterisation Facility (MC2) at the University of Bath (https://doi.org/10.15125/mx6j-3r54) for technical support and assistance in this work. Funding provided by National Institute on Drug Abuse (NIDA) (Grants R01 DA07315 and R37 DA033397.

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Organic Chemistry

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10.1039/d5md00685fLicence: CC BY

Cite this

Ostovar, M., Olsen, K., Cami-Kobeci, G., Traynor, J. R., Jeramaz, L., Kirton, S. B., & Husbands, S. M. (2026). Synthesis and evaluation of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydromorphinone derivatives: mixed partial agonists at mu opioid and nociception/orphanin FQ peptide receptors. RSC Medicinal Chemistry, 17(4), 1950-1960. https://doi.org/10.1039/d5md00685f

Synthesis and evaluation of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydromorphinone derivatives: mixed partial agonists at mu opioid and nociception/orphanin FQ peptide receptors. / Ostovar, Mehrnoosh; Olsen, Keith; Cami-Kobeci, Gerta et al.
In: RSC Medicinal Chemistry, Vol. 17, No. 4, 01.04.2026, p. 1950-1960.

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

Ostovar, M, Olsen, K, Cami-Kobeci, G, Traynor, JR, Jeramaz, L, Kirton, SB & Husbands, SM 2026, 'Synthesis and evaluation of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydromorphinone derivatives: mixed partial agonists at mu opioid and nociception/orphanin FQ peptide receptors', RSC Medicinal Chemistry, vol. 17, no. 4, pp. 1950-1960. https://doi.org/10.1039/d5md00685f

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Synthesis and evaluation of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydromorphinone derivatives: mixed partial agonists at mu opioid and nociception/orphanin FQ peptide receptors

Abstract

Data Availability Statement

Funding

ASJC Scopus subject areas

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