Indole compounds with N -ethyl morpholine moieties as CB2 receptor agonists for anti-inflammatory management of pain: synthesis and biological evaluation

The CB2 receptor plays a crucial role in analgesia and anti-inflammation. To develop novel CB2 agonists with high efficacy and selectivity, a series of indole derivatives with -ethyl morpholine moieties (compounds ) were designed, synthesized and biologically evaluated. Compounds , , , and exhibited...

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Veröffentlicht in:MedChemComm 2019-11, Vol.10 (11), p.1935-1947
Hauptverfasser: Li, Jiaojiao, Ji, Jing, Xu, Ruibo, Li, Zhengfu
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Sprache:eng
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Zusammenfassung:The CB2 receptor plays a crucial role in analgesia and anti-inflammation. To develop novel CB2 agonists with high efficacy and selectivity, a series of indole derivatives with -ethyl morpholine moieties (compounds ) were designed, synthesized and biologically evaluated. Compounds , , , and exhibited high CB2 receptor affinity at low nanomolar concentrations and good receptor selectivity (EC (CB1)/EC (CB2) greater than 1000). The most active compound, compound , was more potent than the standard drug GW405833 for agonistic action on the CB2 receptor. More importantly, in a rat model for CFA-induced inflammatory hyperalgesia, compound had a potent anti-inflammatory pain effect within 12 hours after administration. At the 1 h time point, compound had a dose-dependent reversal for hyperalgesia with an estimated ED value of 1.097 mg kg . Moreover, compound significantly suppressed the pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in CFA-induced lesions. These protective effects of compound on inflammatory pain were superior to those of GW405833, suggesting that compound may be a promising therapeutic drug that needs further validation.
ISSN:2040-2503
2040-2511
DOI:10.1039/c9md00173e