Synthesis and structure-activity relationships of 3,5-disubstituted 4,5-dihydro-6H-imidazo[1,5-a][1,4]benzodiazepin-6-ones at diazepam-sensitive and diazepam-insensitive benzodiazepine receptors

• Published in: Journal of medicinal chemistry 1993-02, Vol.36 (4), p.479-490
• Main Authors: Ananthan, Subramaniam, Clayton, Sarah D, Ealick, Steven E, Wong, Garry, Evoniuk, Gary E, Skolnick, Phil
• Format: Article
• Language: English
• Subjects: Animals; Benzodiazepinones - chemical synthesis; Benzodiazepinones - chemistry; Benzodiazepinones - metabolism; Binding Sites; Cell Membrane - metabolism; Cerebellum - metabolism; Cerebral Cortex - metabolism; Chemistry; Crystallization; Diazepam - pharmacology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Male; Mice; Models, Molecular; Molecular Structure; Organic chemistry; Preparations and properties; Receptors, GABA-A - drug effects; Receptors, GABA-A - metabolism; Structure-Activity Relationship; X-Ray Diffraction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00056a008

A series of imidazobenzodiazepin-6-ones possessing varying substituents at the 3- and 5-positions were synthesized and evaluated for their affinities at diazepam-sensitive (DS) and diazepam-insensitive (DI) benzodiazepine receptors (BzR) in rat cortical and cerebellar membranes. Replacement of an ester substituent at the 3-position with a carbamate, acetylamino, formylamino, isothiocyanato, 2-oxazolinyl, 2-benzoxazolyl, or p-tolylsulfonyl groups lead to > 100-fold reductions in affinity at both DS and DI BzR. Replacement of a methyl group on the nitrogen at the 5-position with propyl, allyl, or phenethyl groups also led to significant reductions in affinity at both BzR isoforms. However, incorporation of a benzyl group yields ligands (11f,h,i and 14a-c) with moderate to high affinities at DS BzR, suggesting the presence of a hydrophobic pocket at the receptor site. Introduction of chlorine at the 7-position enhances ligand affinity at DS BzR while chlorine at the 8-position decreases affinity (IC50: 11f, 9.3 nM; 11h, 2.4 nM; 11i, 37.8 nM). In contrast, chlorine substitution at the 7- as well as the 8-position increases affinity at DI BzR (Ki: 11f, 112 nM; 11h, 20.2 nM; 11i, 10.9 nM). Compound 11 is among the few described high affinity DI-site ligands with a selectivity comparable to that of Ro 15-4513. Despite their in vitro affinities, compounds 11f, 11h, and 11i exhibit low in vivo activities that may be attributable to unfavorable metabolic or pharmacokinetic properties.