Validation of a histamine H3 receptor model through structure–activity relationships for classical H3 antagonists

Histamine H3 receptor is a G protein-coupled receptor whose activation inhibits the synthesis and release of histamine and other neurotransmitters from nerve endings and is involved in the modulation of different central nervous system functions. H3 antagonists have been proposed for their potential usefulness in diseases characterized by impaired neurotransmission and they have demonstrated beneficial effects on learning and food intake in animal models. In the present work, a 3D model of the rat histamine H3 receptor, built by comparative modeling from the crystallographic coordinates of bovine rhodopsin, is presented with the discussion of its ability to predict the potency of known and new H3 antagonists. A putative binding site for classical, imidazole-derived H3 antagonists was identified by molecular docking. Comparison with a known pharmacophore model and the binding affinity of a new rigid H3 antagonist (compound 1, pKi = 8.02) allowed the characterization of a binding scheme which could also account for the different affinities observed in a recently reported series of potent H3 antagonists, characterized by a 2-aminobenzimidazole moiety. Molecular dynamics simulations were employed to assess the stability and reliability of the proposed binding mode. Two new conformationally constrained benzimidazole derivatives were prepared and their binding affinity was tested on rat brain membranes; compound 9, designed to reproduce the conformation of a known potent H3 antagonist, showed higher potency than compound 8, as expected from the binding scheme hypothesized.

Figure optionsDownload as PowerPoint slide