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 N-ethyl
morpholine moieties (compounds 1-56) were designed, synthesized and biologically evaluated. Compounds 1, 2, 3, 46 and 53 exhibited high
CB2 receptor affinity at low nanomolar concentrations and good receptor selectivity (EC50(CB1)/EC50(CB2) greater than 1000). The most active compound, compound 2, was more potent than the standard
drug GW405833 for in vitro agonistic action on the
CB2 receptor. More importantly, in a rat model for CFA-induced inflammatory
hyperalgesia, compound 2 had a potent anti-inflammatory
pain effect within 12 hours after administration. At the 1 h time point, compound 2 had a dose-dependent reversal for
hyperalgesia with an estimated ED50 value of 1.097 mg kg-1. Moreover, compound 2 significantly suppressed the pro-inflammatory
cytokines (IL-1β, IL-6 and TNF-α) in CFA-induced lesions. These protective effects of compound 2 on inflammatory
pain were superior to those of
GW405833, suggesting that compound 2 may be a promising therapeutic
drug that needs further validation.