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

• Published in: Journal of medicinal chemistry Vol. 36; no. 8; pp. 1001 - 1006
• Main Authors: Gu, Zi Qiang, Wong, Garry, Dominguez, Celia, de Costa, Brian R, Rice, Kenner C, Skolnick, Phil
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.04.1993; Amer Chemical Soc
• Subjects: Animals; Benzodiazepines - chemical synthesis; Benzodiazepines - chemistry; Benzodiazepines - metabolism; Binding Sites; Brain - drug effects; Brain - metabolism; Chemistry; Chemistry, Medicinal; Esters; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - metabolism; Life Sciences & Biomedicine; Male; Organic chemistry; Pharmacology & Pharmacy; Preparations and properties; Rats; Rats, Sprague-Dawley; Receptors, GABA-A - drug effects; Receptors, GABA-A - metabolism; Science & Technology; ETHANOL; ANTAGONIST; BINDING; ALCOHOL SENSITIVITY; RO 15-4513; Ester; Cyclization; Isotope labelling; Structure activity relation; Angular nitrogen heterocycle; Lactam; Affinity; Aromatic compound; Benzodiazepine receptor; Selectivity; Tricyclic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00060a007

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 tertbutyl ester compound 8 displayed the highest affinity (K(i) = 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 (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.