Chemokine receptor antagonists with α 1 -adrenergic receptor blocker activity.

Objectives Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C-C motif) receptor 2 (CCR2) antagonist RS504393 is known to compete with ligand binding to α1-adrenoceptors, we tested a panel of 10 CCR antagonists for interactions with α1-adrenoceptors to evaluate potential cardiovascular activities and side-effect profiles. Methods The PRESTO-Tango β-arrestin recruitment assay was utilized to test whether the CCR antagonists interfere with α1b-AR activation upon stimulation with phenylephrine. Pressure myography with isolated rat resistance arteries was employed to assess their effects on phenylephrine-induced vasoconstriction. The following antagonists were tested: CCR1-BX471, BX513, BI639667; CCR2-RS504393, INCB3284; CCR3-SB328437; and CCR4-AZD2098, and C021; CCR5-Maraviroc; CCR10-BI6901. The pan-α1-adrenoceptor antagonist prazosin was used as control. Results Among the CCR antagonists tested, RS504393, BX513, and C021 inhibited phenylephrine-induced β-arrestin recruitment to α1b-adrenoceptor and phenylephrine-induced vasoconstriction. While RS504393 functioned as a competitive α1-adrenoceptor blocker, BX513 and C021 functioned as noncompetitive α1-adrenoceptor antagonists in both assay systems. Furthermore, RS504393, BX513, and C021 dose-dependently dilated arteries that were fully preconstricted with phenylephrine. Conclusions Our data suggest that CCR antagonists should be screened for cross-reactivity with α1-adrenoceptors to exclude potential adverse cardiovascular effects when used as anti inflammatory drugs.