A qualitative model for the histamine H-3 receptor explaining agonistic and antagonistic activity simultaneously

A pharmacophore model for histamine H-3 ligands is derived that reveals the putative interaction of both H-3 agonists and antagonists with an aspartat e residue of the receptor. This interaction is determined by applying the d ensity functional theory implemented in a program package adapted for paral lel computers. The model reveals a molecular determinant explaining efficac y as the conformation of the aspartic acid residue differs according to whe ther it is binding to agonists or antagonists. The differences in structure -activity relationships (SAR) observed for the lipophilic tails of differen t classes of H-3 antagonists are now explained, since the model reveals two distinct lipophilic pockets available for antagonist binding.