Mutational Analysis of the Antagonist-binding Site of the Histamine H1 Receptor*

We combined in a previously derived three-dimensional model of the histamine H1 receptor (Ter Laak, A. M., Timmerman, H., Leurs, H., Nederkoorn, P. H. J., Smit, M. J., and Donne-Op den Kelder, G. M. (1995) J. Comp. Aid. Mol. Design. 9, 319–330) a pharmacophore for the H1 antagonist binding site (Ter Laak, A. M., Venhorst, J., Timmerman, H., and Donné-Op de Kelder, G. M. (1994) J. Med. Chem. 38, 3351–3360) with the known interacting amino acid residue Asp116 (in transmembrane domain III) of the H1 receptor and verified the predicted receptor-ligand interactions by site-directed mutagenesis. This resulted in the identification of the aromatic amino acids Trp167, Phe433, and Phe436 in transmembrane domains IV and VI of the H1 receptor as probable interaction points for the trans-aromatic ring of the H1 antagonists. Subsequently, a specific interaction of carboxylate moieties of two therapeutically important, zwitterionic H1 antagonists with Lys200 in transmembrane domain V was predicted. A Lys200 → Ala mutation results in a 50- (acrivastine) to 8-fold (d-cetirizine) loss of affinity of these zwitterionic antagonists. In contrast, the affinities of structural analogs of acrivastine and cetirizine lacking the carboxylate group, triprolidine and meclozine, respectively, are unaffected by the Lys200 → Ala mutation. These data strongly suggest that Lys200, unique for the H1receptor, acts as a specific anchor point for these “second generation” H1 antagonists.

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