Pharmacological Profile of Histaprodifens at Four Recombinant Histamine H1 Receptor Species Isoforms

There are differences in the pharmacological properties of phenylhistamines and histaprodifens between guinea pig histamine H₁ receptor (gpH₁R) and human histamine H₁ receptor (hH₁R). The aim of this study was to analyze species differences in more detail, focusing on histaprodifen derivatives and including the bovine histamine H₁ receptor (bH₁R) and rat histamine H₁ receptor (rH₁). H₁R species isoforms were coexpressed with the regulator of G protein signaling RGS4 in Sf9 insect cells. We performed [³H]mepyramine binding assays and steady-state GTPase assays. For a novel class of histaprodifens, the chiral histaprodifens, unique species differences between hH₁R, bH₁R, rH₁R, and gpH₁R were observed. The chiral histaprodifens 8R and 8S were both partial agonists at gpH₁R, but only 8R was a partial agonist at the other H₁R species isoforms. An additional phenyl group in chiral histaprodifens 10R and 10S, respectively, resulted in a switch from agonism at gpH₁Rto antagonism at hH₁R, bH₁R, and rH₁R. In general, histaprodifens showed the order of potency hH₁R < bH₁R < rH₁R < gpH₁R. An active-state model of gpH₁R was generated with molecular dynamics simulations. Dimeric histaprodifen was docked into the binding pocket of gpH₁R. Hydrogen bonds and electrostatic interactions were detected between dimeric histaprodifen and Asp-116, Ser-120, Lys-187, Glu-190, and Tyr-432. We conclude the following: 1) chiral histaprodifens interact differentially with H₁R species isoforms; 2) gpH₁R and rH₁R, on one hand, and hH₁R and bH₁R, on the other hand, resemble each other structurally and pharmacologically; and 3) histaprodifens interact with H₁R at multiple sites