Inhibitory Effect of the 4-Aminotetrahydroquinoline Derivatives, Selective Chemoattractant Receptor-Homologous Molecule Expressed on T Helper 2 Cell Antagonists, on Eosinophil Migration Induced by Prostaglandin D₂

Abstract

Prostaglandin (PG) D 2 , a major cyclooxygenase metabolite generated from immunologically stimulated mast cells, is known to induce activation and chemotaxis in eosinophils, basophils, and T helper 2 (Th2) lymphocytes via a newly identified PGD 2 receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). CRTH2 is hypothesized to play an important role in the outcome of allergic responses. However, the absence of selective CRTH2 antagonists has prevented the elucidation of the role of CRTH2 in pathogenesis of allergic diseases. We now report compounds discovered as selective CRTH2 antagonists, (2R*,4S*)-N-(1-benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylisobutyramide (K117) and (2R*,4S*)-N-(1-benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylcyclopropanecarboxamide (K604). K117 and K604 have inhibitory effects on human CRTH2 with K i values of 5.5 and 11 nM, respectively. The effect of these compounds is CRTH2-specific with no crossreactivity against 15 other receptors and four arachidonic acidmetabolizing enzymes. K117 and K604 has no effect on the basal Ca 2ϩ level and inhibited the Ca 2ϩ response induced by PGD 2 in 293EBNA cells expressing human CRTH2. Also, K117 and K604 inhibit PGD 2 -induced human eosinophil chemotaxis with IC 50 values of 7.8 and 42.2 nM, respectively, but they do not inhibit the CC-chemokine receptor 3 agonist eotaxin-induced chemotaxis. These results indicate that K117 and K604 are highly potent and selective antagonists for human CRTH2. These compounds have possibilities to become useful tools to explore CRTH2 functions in allergic diseases.

On the Mechanism of Interaction of Potent Surmountable and Insurmountable Antagonists with the Prostaglandin D2 Receptor CRTH2

“…We therefore analyzed antagonist behavior in a more natural ex vivo cell system, using human eosinophils, which endogenously express CRTH2 as a model system. Purified human eosinophils undergo shape change upon exposure to PGD2 that is characterized by a biphasic dose-response curve (Hirai et al, 2001;Bohm et al, 2004); the response is known to be mediated via CRTH2, because it is sensitive to blockade with CRTH2 antagonists (Bohm et al, 2004;Mathiesen et al, 2005;Mimura et al, 2005). Our study confirmed the inhibitive effect of ramatroban, which led to concentration-dependent dextral shifts of the PGD2-mediated shape change responses, consistent with classic competitive antagonism (Fig.…”

The roles of the prostaglandin D2 receptors DP1 and CRTH2 in promoting allergic responses

“…This observation has led to the identification of ramatroban analogues, which are potent CRTH2 antagonists devoid of TP activity ( Ulven and Kostenis, 2005 ). The only non‐acid CRTH2 antagonists so far described are 4‐aminotetrahydroquinoline derivatives as exemplified by K117 and K604 ( Mimura et al , 2005 ).…”

Agonist and Antagonist Effects of 15R-Prostaglandin (PG) D2and 11-Methylene-PGD2on Human Eosinophils and Basophils

“…Other indolic compounds with selective DP 2 receptor antagonist activities have also recently been reported (Armer et al, 2005;Birkinshaw et al, 2006). A series of tetrahydroquinoline derivatives have also been identified as selective DP 2 antagonists (Mimura et al, 2005).…”