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 N -ethyl morpholine moieties (compounds 1-56 ) were designed, synthesized and biologically evaluated. Compounds 1 , 2 , 3 ,...
Saved in:
Published in | MedChemComm Vol. 1; no. 11; pp. 1935 - 1947 |
---|---|
Main Authors | , , , |
Format | Journal Article |
Published |
13.11.2019
|
Online Access | Get full text |
Cover
Loading…
Summary: | 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. |
---|---|
Bibliography: | 10.1039/c9md00173e Electronic supplementary information (ESI) available. See DOI |
ISSN: | 2040-2503 2040-2511 |
DOI: | 10.1039/c9md00173e |