In previous blogs, we introduced two CRTH2 receptor antagonists, BI-671800 and MK-8318. They both have potential to treat allergic diseases, like asthma.
Today, we would like to introduce a potent and selective synthetic agonist at the CRTH2 receptor, L 888607. It was the first synthetic potent and selective CRTH2 agonist, which has been found over 10 years. A study from Franc¸ ois G. Gervais firstly discovered and identified the CRTH2 receptor agonist.
Firstly, in the study, the authors showed that L-888607 exhibited subnanomolar affinity for the human CRTH2 receptor, high selectivity over all other prostanoid receptors and other receptors tested. As a result, L 888607 displayed Ki values of 0.8 nM, 2331 nM, 283 nM, 8748 nM, 1260 nM, 4634 nM, 10018 nM and 14434 nM for CRTH2/DP2 receptor, DP/DP1 receptor, TP receptor, EP2 receptor, EP3-III receptor, EP4 receptor, FP receptor, and IP receptor, respectively.
Additionally, it also displayed agonistic activity on recombinant and endogenously expressed CRTH2 receptor, and relative stable in vivo.
As a result, in vitro, L-888,607 was capable of inducing a morphological response in freshly isolated and purified human eosinophils.
In vivo, a single dose [5 mg/kg in 60% (v/v) polyethylene glycol 200] of L 888607 was given intravenously via the saphenous vein or a single dose (20 mg/kg in 60% (v/v) polyethylene glycol 400) was given orally by gavage. No obvious side effects were observed (n of four in each case).
To conclude, L 888607 thus represents a suitable tool to investigate the in vivo function of CRTH2.
Gervais FG, et al. Identification of a potent and selective synthetic agonist at the CRTH2 receptor. Mol Pharmacol. 2005 Jun;67(6):1834-9.