Synthesis, biological evaluation, and SAR studies of 14β-phenylacetyl substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones derivatives: Ligands with mixed NOP and opioid receptor profile

Vinod Kumar; Willma E. Polgar; Gerta Cami-Kobeci; Mark P. Thomas; Taline V. Khroyan; Lawrence Toll; Stephen M. Husbands

doi:10.3389/fpsyt.2018.00430

Synthesis, biological evaluation, and SAR studies of 14β-phenylacetyl substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones derivatives: Ligands with mixed NOP and opioid receptor profile

Vinod Kumar, Willma E. Polgar, Gerta Cami-Kobeci, Mark P. Thomas, Taline V. Khroyan, Lawrence Toll, Stephen M. Husbands

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

2 Citations (SciVal)

Abstract

A series of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydronoroxymorphinone compounds has been synthesized and evaluated for affinity and efficacy for mu (MOP), kappa (KOP), and delta (DOP) opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. The majority of the new ligands displayed high binding affinities for the three opioid receptors, and moderate affinity for NOP receptors. The affinities for NOP receptors are of particular interest as most classical opioid ligands do not bind to NOP receptors. The predominant activity in the [35S]GTPγS assay was partial agonism at each receptor. The results are consistent with our prediction that an appropriate 14β side chain would access a binding site within the NOP receptor and result in substantially higher affinity than displayed by the parent compound naltrexone. Molecular modeling studies, utilizing the recently reported structure of the NOP receptor, are also consistent with this interpretation.

Original language	English
Article number	430
Pages (from-to)	1-10
Number of pages	10
Journal	Frontiers in Psychiatry
Volume	9
Issue number	SEP
DOIs	https://doi.org/10.3389/fpsyt.2018.00430
Publication status	Published - 19 Sept 2018

Funding

This work was funded by the National Institutes of Health National Institute on Drug Abuse grants DA20469 and DA07315 (SH) and DA023281 (LT). MT was supported by the Wellcome Trust (Programme Grant 082837 to BVL Potter, University of Bath).

Keywords

Analgesics
Kappa opioid receptor
Mu opioid receptors
Nociceptin
Opioid
ORL-1

ASJC Scopus subject areas

Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3389/fpsyt.2018.00430Licence: CC BY

Cite this

Kumar, V., Polgar, W. E., Cami-Kobeci, G., Thomas, M. P., Khroyan, T. V., Toll, L., & Husbands, S. M. (2018). Synthesis, biological evaluation, and SAR studies of 14β-phenylacetyl substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones derivatives: Ligands with mixed NOP and opioid receptor profile. Frontiers in Psychiatry , 9(SEP), 1-10. Article 430. https://doi.org/10.3389/fpsyt.2018.00430

Synthesis, biological evaluation, and SAR studies of 14β-phenylacetyl substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones derivatives: Ligands with mixed NOP and opioid receptor profile. / Kumar, Vinod; Polgar, Willma E.; Cami-Kobeci, Gerta et al.
In: Frontiers in Psychiatry , Vol. 9, No. SEP, 430, 19.09.2018, p. 1-10.

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

Kumar, V, Polgar, WE, Cami-Kobeci, G, Thomas, MP, Khroyan, TV, Toll, L & Husbands, SM 2018, 'Synthesis, biological evaluation, and SAR studies of 14β-phenylacetyl substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones derivatives: Ligands with mixed NOP and opioid receptor profile', Frontiers in Psychiatry , vol. 9, no. SEP, 430, pp. 1-10. https://doi.org/10.3389/fpsyt.2018.00430

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Synthesis, biological evaluation, and SAR studies of 14β-phenylacetyl substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones derivatives: Ligands with mixed NOP and opioid receptor profile

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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Fingerprint

Stephen Husbands

Cite this

Synthesis, biological evaluation, and SAR studies of 14β-phenylacetyl substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones derivatives: Ligands with mixed NOP and opioid receptor profile

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Profiles

Stephen Husbands

Cite this