Molecular structure of Ro15-1788 and a model for the binding of benzodiazepine receptor ligands. Structural identification of common features in antagonists.

Ligands that bind to the benzodiazepine receptor have three possible effects. The ligand can be an agonist and reduce anxiety, an antagonist and have no biological effect, or an inverse agonist and promote convulsions. This receptor complex is unique in its spectrum of response to ligands, and conformational changes in the receptor are implicated. The x-ray crystal structure of an imidazobenzodiazepine antagonist ligand, Ro15-1788, was determined and compared to the structures of the 1,4-benzodiazepine agonists and to two other types of antagonists, beta-carbolines and a pyrazoloquinolinone, CGS-8216. The antagonists were found to have similar arrangements of binding features including an aromatic ring, a carbonyl oxygen atom, and a hydrophobic side chain. The structures of these antagonists could be superimposed in a model binding site with three common features for all of the antagonists and a fourth hydrogen-bonding site for the pure antagonists (or inverse agonists), the beta-carbolines, and CGS-8216. A comparison of the shapes of the antagonist benzodiazepine, Ro15-1788, and several agonists showed that RO15-1788 has a unique azepine ring conformation that distorts the usual arrangement of the aromatic A ring, carbonyl oxygen atom, and imine N atom of the agonists. A conformational adjustment in the receptor would be required to accommodate both of these types of ligands. A summary of the superpositions of typical agonists and the antagonists leads to a model with 7 conformationally mobile binding points. Inverse agonists are distinguished from antagonists by the length of the hydrophobic side chain. Antagonists are distinguished from agonists in part by the lack of a binding feature similar to the imine N atom of the diazepine ring. This model accounts for the key features found in ligands for the benzodiazepine receptor and provides an explanation for the spectrum of responses elicited by receptor binding.