Mutagenesis of the human histamine H1 receptor and design of new antihistamine agents
Differding, E.; Gillard, M.; Moguilevsky, N.; Varsalona, F.; Noyer, M.; Daliers, J.; Goldstein, S.; Neuwels, M.; Lassoie, M.A.; Guillaume, J.P.; Bascour, M.; Bollen, A.; Hénichart, J.P.
Journal de Pharmacie de Belgique 51(3): 155-160
1996
ISSN/ISBN: 0047-2166 PMID: 8778348 Document Number: 468798
The binding cavity of histamine and histamine antagonists is explored using site directed mutagenesis of the human histamine H1 receptor and the amino acids involved in ligand binding are identified. Whereas Asp107 and Phe199 are important for both agonists and antagonists, two additional amino acids (Asn198 and Trp103) are required for efficient histamine binding. The binding site of antagonists is 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.