Quantitative structure-retention relationships in the examination of the topography of the binding site of antihistamine drugs on alpha 1-acid glycoprotein.

Quantitative relationships between the structure of antihistamine drugs (AHD) and their retention on an alpha 1-acid glycoprotein (AGP) HPLC column (QSRR) were studied in order to identify characteristic structural features of the binding site for AHD on AGP. The hydrophobicity of AHD was determined by HPLC on an immobilized artificial membrane (IAM) column. A highly significant QSRR equation was obtained which describes the retention of AHD on AGP in terms of the chromatographically determined hydrophobicity parameter, electron excess charge on the aliphatic nitrogen and a molecular size descriptor. The topography of the AHD-binding site on AGP was suggested to be a conical pocket with lipophilic regions at the mouth of the receptor and an anionic region close to the spike of the cone. Protonated aliphatic nitrogen is supposed to guide a drug molecule towards the anionic region of the binding site. Hydrophobic aryl moieties provide anchoring of the molecule in the lipophilic regions of the binding site. Steric hindrance prevents the molecule from plunging into the binding site.