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

• Published in: MedChemComm Vol. 1; no. 11; pp. 1935 - 1947
• Main Authors: Li, Jiaojiao, Ji, Jing, Xu, Ruibo, Li, Zhengfu
• Format: Journal Article
• Published: 13.11.2019
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c9md00173e

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 (EC 50 (CB1)/EC 50 (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 ED 50 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. A series of indole compounds were designed and synthesized as CB2 agonist with high efficacy and selectivity.