A qualitative model for the histamine H3 receptor explaining agonistic and antagonistic activity simultaneously.
A pharmacophore model for histamine H3 ligands is derived that reveals the putative interaction of both H3 agonists and antagonists with an aspartate residue of the receptor. This interaction is determined by applying the density functional theory implemented in a program package adapted for parallel computers. The model reveals a molecular determinant explaining efficacy as the conformation of the aspartic acid residue differs according to whether it is binding to agonists or antagonists. The differences in structure-activity relationships (SAR) observed for the lipophilic tails of different classes of H3 antagonists are now explained, since the model reveals two distinct lipophilic pockets available for antagonist binding.
de Esch
I J
IJ
Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands. Iwan.deEsch@ddg.phar.cam.ac.uk
Timmerman
H
H
Menge
W M
WM
Nederkoorn
P H
PH
D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D017442:Histamine Agonists / Q000737:chemistry* / Q000378:metabolism; D006633:Histamine Antagonists / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D017982:Receptors, Biogenic Amine / Q000737:chemistry / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008024:Ligands; D017982:Receptors, Biogenic Amine; D018100:Receptors, Histamine H3; D001224:Aspartic Acid; C029899:imidazole