UNIQUE BINDING POCKET FOR KW-4679 IN THE HISTAMINE H-1 RECEPTOR

The histamine H-1 receptor has an aspartate (Asp) residue in transmemb rane helix 3 (TM3), which is well-conserved among biogenic amine recep tors. The Asp residue is one of the most crucial amino acids for ligan d binding. The tested histamine H, receptor antagonists with tri- and tetracyclic structures were not selective for histamine H-1 receptors and showed affinity for several other biogenic amine receptors. In con trast, KW-4679 ((Z)-11-[3-(dimethylamino)propylidene]-6 acid hydrochlo ride), a tricyclic compound, was a selective histamine H-1 receptor an tagonist. [H-3]KW-4679 had high affinity (K-d value of 2.5 +/- 0.12 nM ) for wild-type human histamine H-1 receptors. In the [H-3]KW-4679 bin ding assay, replacement of Asp(107) by alanine by site-directed mutage nesis greatly reduced the affinities (280-2100-fold) of tri- and tetra cyclic compounds, whereas this mutation led to a comparatively small r eduction (14-fold) in KW-4679 affinity. These results demonstrate that the tested tri-and tetracyclic histamine H-1 receptor antagonists whi ch have a tight interaction with the Asp residue are not selective for the histamine H-1 receptor. Furthermore, the high selectivity of KW-4 679 might be explained by a unique binding pocket, which consists of t he Asp residue and other acceptor sites, in the histamine H-1 receptor . (C) 1998 Elsevier Science B.V.