Benzodiazepines produce most, if not all, of their numerous effects on the central nervous system (CNS) primarily by increasing the function of those chemical synapses that use gamma-amino butyric acid (GABA) as transmitter. This specific enhancing effect on GABAergic synaptic inhibition is initiated by the interaction of benzodiazepines with membrane proteins of certain central neurones, to which drugs of this chemical class bind with high affinity and specificity. The molecular processes triggered by the interaction of these drugs with central benzodiazepine receptors, and which result in facilitation of GABAergic transmission, are still incompletely understood. Theoretically, benzodiazepines could mimic the effect of hypothetical endogenous ligands for the benzodiazepine receptors, although there is no convincing evidence for their existence; in vitro studies indicate that benzodiazepines might compete with a modulatory peptide which is present in the supramolecular assembly formed by GABA receptor, chloride ionophore and benzodiazepine receptor and which reduces the affinity of the GABA receptor for its physiological ligand. The mechanisms of action of benzodiazepines at the molecular level are likely to be better understood following our recent discovery of benzodiazepine derivatives, whose unique pharmacological activity is to prevent or abolish in a highly selective manner at the receptor level all the characteristic centrally mediated effects of active benzodiazepines. Here, we describe the main properties of a representative of this novel class of specific benzodiazepine antagonists.

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Several 1,4-diazepines were recently reported to bind with high affinities to the "diazepam-insensitive" (DI) isoform of the benzodiazepine receptor (BzR) (Korpi, E.R.; Uusi-Oukari, M.; Wegelius, K. Eur. J. Pharm. 1992, 213, 323-329. Wong, G.; Skolnick, P. Eur. J. Pharmacol. Mol. Pharm. Sec. 1992, 225, 63-68). However, only the putative ethanol antagonist 1 (Ro 15-4513) displayed modest selectivity for the DI site compared to other "diazepam-sensitive" (DS) BzR isoforms. In order to probe the requirements for selective, high-affinity binding to the DI site, the affinities of 47 benzodiazepines have been determined at both DI and DS BzR sites. In addition, single X-ray crystallographic analyses for three of these derivatives, 5 (Ro 17-1812), 6 (Ro 16-6028), and 42 (Ro 14-5974), are reported. The radioligand binding studies reveal that modifications to the 3-, 7-, and 8-positions of 6-oxoimidazo[1,5-alpha] [1,4]benzodiazepines have a marked influence on the Ki(DI)/Ki(DS) ratios. In order to more precisely determine the structural requirements for both high affinity and selectivity at DI BzR relative to DS, 3D-QSAR analyses were carried out on ligand affinities at both of these BzR isoforms. This analysis was based, in part, on the new X-ray crystallographic data. Satisfactory cross-validated regression equations were obtained individually for the logarithms of ligand affinities at DI and DS as well as for the differences of the logarithms of their affinities at these two isoforms (cross-validated R2 > 0.70 for all three regression equations). The steric and electrostatic 3D-QSAR DI and DS maps are in qualitative accord with the structure-activity relationship (SAR) data. Furthermore, the DI and DI/DS maps may be useful in the design of ligands with enhanced DI affinity and DI/DS selectivity, respectively.

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