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A Qualitative Model for the Histamine H 3 Receptor Explaining Agonistic and Antagonistic Activity Simultaneously
Author(s) -
de Esch Iwan J. P.,
Timmerman Henk,
Menge Wiro M. P. B.,
Nederkoorn Paul H. J.
Publication year - 2000
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/1521-4184(20008)333:8<254::aid-ardp254>3.0.co;2-g
Subject(s) - pharmacophore , histamine h3 receptor , chemistry , antagonist , stereochemistry , molecular model , histamine , receptor , structure–activity relationship , residue (chemistry) , amino acid residue , biochemistry , pharmacology , peptide sequence , biology , in vitro , gene
A pharmacophore model for histamine H 3 ligands is derived that reveals the putative interaction of both H 3 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 H 3 antagonists are now explained, since the model reveals two distinct lipophilic pockets available for antagonist binding.