Abstract
WIN 51708 is a nonpeptide antagonist of the neurokinin (NK)-1 (substance P) receptor that possesses a dramatically higher affinity for the rat NK-1 receptor, compared with the human NK-1 receptor. This selectivity is the opposite of the selectivity displayed by CP-96,345 and is much greater in magnitude than the selectivity of RP 67580. The naturally occurring peptide agonist substance P shows no such species selectivity. To determine the molecular basis for the species selectivity of WIN 51708, a series of chimeric and point-mutated NK-1 receptors were created and functionally expressed in Chinese hamster ovary cells. Residue 97 in the first extracellular loop and residue 290 in the seventh putative transmembrane domain are critical determinants for the selectivity of WIN 51708 for the rat over the human NK-1 receptor. Although mutation of either residue 97 or residue 290 in the rat NK-1 receptor is sufficient for a low, human-like affinity for WIN 51708, both of these residues must be simultaneously mutated in the human NK-1 receptor to allow nearly rat wild-type affinity for this antagonist. This suggests that the binding environment for WIN 51708 in the rat NK-1 receptor differs, at least in part, from the binding environment in the human NK-1 receptor. In addition, although residue 290 is critical for the species selectivity of WIN 51708 and CP-96,345, residue 97 does not play a role in the species selectivity of CP-96,345. These data support a model in which the binding environments for WIN 51708 and CP-96,345 in part differ.
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