Species selectivity of a small molecule antagonist for the CCR1 chemokine receptor

The species specificity of a small molecule antagonist for the human CCR1 c hemokine receptor, 2-2-diphenyl-5-(4-chlorophenyl)piperidin-1-yl)valeronitr ile (CCR1 antagonist 1), has been examined using cloned CCR1 receptors from various species. The compound was able to bind to rabbit, marmoset, and hu man CCR1, and was able to block the functional activation of these receptor s. However, it failed to significantly displace radiolabeled macrophage inf lammatory protein-1 alpha (MIP-1 alpha) binding to mouse CCR1 at concentrat ions up to 10 mu M. These data suggested that the antagonist binding site i s well-conserved in rabbit, marmoset and human CCR1, but not in mouse CCR1. The functional selectivity and mechanism of action for CCR1 antagonist 1 w ere further characterized. CCR1 antagonist 1 blocked the increase in intrac ellular Ca2+ stimulated by CCR1 agonists, but had no effect on N-formyl-Met -Leu-Phe (FMLP), monocyte chemotactic protein-1 (MCP-1) and stromal-derived factor 1 alpha (SDF1 alpha)-induced Ca2+ mobilization, demonstrating funct ional selectivity for CCR1. Since CCR1 antagonist 1 is a functional antagon ist of marmoset and rabbit CCR1 receptors, it should be possible to test it s efficacy in animal models of disease. (C) 2000 Elsevier Science B.V. All rights reserved.