Rational Drug Design Using Mammalian Cell Lines Expressing Site-Directed Mutants of the Human H1 Histaminic Receptor

The binding cavity of histamine and histamine antagonists has been explored using site-directed mutagenesis of the human histamine H1 receptor and the amino acids involved in ligand binding have been identified. Whereas Asp107 and Phe199 appeared important for both agonists and antagonists, two additional amino acids (Asn198 and Trp103) were required for efficient histamine binding. The binding site of antagonists was best defined as resulting from a strong ionic bond to Asp107, an orthogonal interaction between one of the aromatic rings with Phe199, and probably a hydrophobic interaction between the second aromatic ring and the lipophilic amino acids of the upper part of TMIV and TMV. This is consistent with structure-activity data of most described antagonists.