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Issue 12, 2018
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Development of selective, fluorescent cannabinoid type 2 receptor ligands based on a 1,8-naphthyridin-2-(1H)-one-3-carboxamide scaffold

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Abstract

Cannabinoid type 2 (CB2) receptor has been implicated in several diseases and conditions, however no CB2 receptor selective drugs have made it to market. The aim of this study was to develop fluorescent ligands as CB2 receptor tools, to enable an increased understanding of CB2 receptor expression and signalling and thereby accelerate drug discovery. Fluorescent ligands have been successfully developed for other receptors, however none with adequate subtype selectivity or imaging properties have been reported for CB2 receptor. A series of 1,8-naphthyridin-2-(1H)-one-3-carboxamides with linkers and fluorophores appended in the N1 and C3-positions were developed. Molecular modelling indicated the C3 cis-cyclohexanol-linked compounds directed the linker out of the CB2 receptor between transmembrane helices 1 and 7. Herein we report fluorescent ligand 32 (hCB2 pKi = 6.33 ± 0.02) as one of the highest affinity, selective CB2 receptor fluorescent ligands reported. Despite 32 displaying poor specific labelling of CB2 receptor, the naphthyridine scaffold with this linker remains highly promising for future development of CB2 receptor tools.

Graphical abstract: Development of selective, fluorescent cannabinoid type 2 receptor ligands based on a 1,8-naphthyridin-2-(1H)-one-3-carboxamide scaffold

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Publication details

The article was received on 07 Sep 2018, accepted on 18 Oct 2018 and first published on 23 Oct 2018


Article type: Research Article
DOI: 10.1039/C8MD00448J
Med. Chem. Commun., 2018,9, 2055-2067
  • Open access: Creative Commons BY license
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    Development of selective, fluorescent cannabinoid type 2 receptor ligands based on a 1,8-naphthyridin-2-(1H)-one-3-carboxamide scaffold

    A. G. Cooper, C. R. M. Oyagawa, J. J. Manning, S. Singh, S. Hook, N. L. Grimsey, M. Glass, J. D. A. Tyndall and A. J. Vernall, Med. Chem. Commun., 2018, 9, 2055
    DOI: 10.1039/C8MD00448J

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