Development of a comprehensive pharmacophore model for the benzodiazepine receptor.
A unified pharmacophore model of the benzodiazepine receptor (BzR) has been developed using the techniques of chemical synthesis, radioligand binding, and receptor mapping. This model is based on 136 different ligands spanning ten structurally diverse classes of compounds and qualitatively accounts for the relative affinities, efficacies, and functional effects (agonism vs. antagonism vs. inverse agonism) displayed by various ligands at the BzR. In addition, the model is expanded to account for the pharmacology of a recently discovered BzR receptor subtype termed the 'Diazepam-Insensitive' (DI) BzR. Moreover, the unified model described here is compared and contrasted with other published pharmacophore models. As previously reported, the synthesis of both partial agonists and partial inverse agonists has been achieved by using parts of this model. Partial agonists are of interest as potentially improved agents for treatment of anxiety disorders, while the partial inverse agonists may furnish important clues for the treatment of age-associated memory impairment.
Zhang
W
W
Department of Chemistry, University of Wisconsin-Milwaukee 53201, USA.
Koehler
K F
KF
Zhang
P
P
Cook
J M
JM
D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D003975:Diazepam / Q000737:chemistry / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006860:Hydrogen Bonding; D008024:Ligands; D008956:Models, Chemical; D008968:Molecular Conformation; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000737:chemistry*; D013329:Structure-Activity Relationship
D002243:Carbolines; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008024:Ligands; D011810:Quinoxalines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; D003975:Diazepam