Synthesis and Evaluation of Imidazobenzodiazepine Esters with High Affinities and Selectivities at "Diazepam-Insensitive" Benzodiazepine Receptors

Article abstract of DOI:10.1021/jm00060a007

A series of imidazo<1,5-a><1,4>benzodiazepine esters have been synthesized with varying esters 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 (K_i = 1.7 nM) for DI within a series of a 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 (K_i = 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.