Journal
MOLECULES
Volume 27, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/molecules27093019
Keywords
neuroblastoma; cannabinoid receptor 2; selective CB2R agonists
Funding
- MIUR (PRIN 2017) [2017SA5837]
- University of Pisa [PRA_2020_58]
- FIRC-AIRC fellowship [24259]
- Natural Sciences and Engineering Research Council (NSERC) Discovery Grant
- NSERC Graduate Scholarship
- Canadian Institutes of Health Research (CIHR)-GlaxoSmithKline (GSK) [2017014]
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This study synthesized and characterized new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. These compounds showed anticancer activity by modulating the cAMP response and modulating ERK1/2 expression through a CB2R-mediated mechanism.
1,8-naphthyridine-3-carboxamide structures were previously identified as a promising scaffold from which to obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds were able to pharmacologically modulate the cAMP response without modulating CB2R-dependent beta-arrestin2 recruitment. These structures were also evaluated for their anti-cancer activity against SH-SY5Y and SK-N-BE cells. They were able to reduce the cell viability of both neuroblastoma cancer cell lines with micromolar potency (IC50 of FG158a = 11.8 mu M and FG160a = 13.2 mu M in SH-SY5Y cells) by a CB2R-mediated mechanism. Finally, in SH-SY5Y cells one of the newly synthesized compounds, FG158a, was able to modulate ERK1/2 expression by a CB2R-mediated effect, thus suggesting that this signaling pathway might be involved in its potential anti-cancer effect.
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