Synthesis and evaluation of imidazo[1,5-a][1,4]benzodiazepine esters with high affinities and selectivities at "diazepam-insensitive" benzodiazepine receptors

Abstract

A series of imidazo[1,5-a][1,4]benzodiazepine esters have been synthesized with varying ester side chains and 8-position substituents. The affinities of these compounds were evaluated at both "diazepam-insensitive" (DI) and diazepam-sensitive (DS) subtypes of the benzodiazepine receptor (BZR). A profound steric effect of the 3-position ester side chain moiety was observed on ligand affinity at DI. In contrast, ester size had a less robust effect on ligand affinity at DS. The tert-butyl ester compound 8 displayed the highest affinity (Ki = 1.7 nM) for DI within a series of 8-chloro esters. Furthermore, halogens at the 8-position resulted in an enhancement of both ligand affinity and selectivity at DI among the series of tert-butyl esters examined. The 8-nitro derivative 23 and 8-isothiocyanato congener 25 had high affinities for both DI and DS but exhibited little subtype selectivity (10.8 and 2.7 nM at DI versus 14 and 3.7 nM at DS, respectively). The 8-azido tert-butyl ester 29 exhibited a significantly higher affinity (Ki = 0.43 nM) and selectivity (DI/DS ratio of 0.2) than the corresponding ethyl ester, the prototypic DI ligand 1 (Ro 15-4513). Among the compounds synthesized, 29 is the highest affinity ligand for DI described to date while its 8-bromo analog 18 is the most selective ligand (DI/DS ratio of 0.17) for this novel BZR subtype.

Heterogeneity of GABAA Receptors: Revived Interest in the Development of Subtype-selective Drugs

“…Most of the classical benzodiazepines, such as diazepam, flunitrazepam, or clonazepam, do not interact with these receptors [4,60,198]. The selectivity of compounds developed for α4βγ2 or α6βγ2 receptors is only weak [199][200][201] and thus, they currently cannot be selectively addressed and the behavioural effects mediated by these receptors are not known. Since most of the benzodiazepine site ligands modulate α1βγ2, α2βγ2, α3βγ2, or α5βγ2 receptors to a more or less similar extent, it is no surprise that the clinical spectrum of action of these compounds is quite similar.…”

The Chemistry of Anthranilic Acid

“…In the cases where X=NO the nitrogen could be deprotected. The most common way of synthesizing compounds of type 98 has been to allow an amino acid (or esters thereof) to attack isatoic anhydride (5) [285,286]. Heating of the AA amide formed induces cyclisation to 98 (Scheme 42).…”

Ligands of the GABAA Receptor Benzodiazepine Binding Site

“…The importance of the ester group substituent at position 3 ( Fig. 2) and the high affinity of the ligand for the DI GABA A subtypes were indicated by SAR and QSAR analyses of imidazobenzodiazepines (26)(27)(28). A DI GABA A receptor pharmacophore ( Fig.…”

“…5, No. 2,1999 LIGANDS OF THE GABA A RECEPTOR BENZODIAZEPINE BINDING SITE 127 (26,27). This observation suggests that a lipophilic pocket within the DI GABA A receptors is juxtaposed to, and interacts with the functional moiety at position 3 of the compound as the ligand leads to the receptor.…”