Indole compounds with -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 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.