Journal Article
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
Ananthan, S; Clayton, SD; Ealick, SE; Wong, G; Evoniuk, GE; Skolnick, P; ,
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804
AMER CHEMICAL SOC
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.
4,5 dihydro 6h imidazo[1,5 a][1,4]benzodiazepin 6 one derivative; 5 benzyl 4,5 dihydro 3 (3 methyl 1,2,4 oxadiazol 5 yl) 6h imidazo[1,5 a][1,4]benzodiazepin 6 one; 5 benzyl 5,6 dihydro 6 oxo 4h imidazo[1,5 a][1,4]benzodiazepine 3 carboxylic acid ethyl ester; 5 benzyl 7 chloro 4,5 dihydro 3 (3 methyl 1,2,4 oxadiazol 5 yl) 6h imidazo[1,5 a][1,4]benzodiazepin 6 one; 5 benzyl 7 chloro 5,6 dihydro 6 oxo 4h imidazo[1,5 a][1,4]benzodiazepine 3 carboxylic acid ethyl ester; 5 benzyl 8 chloro 4,5 dihydro 3 (3 methyl 1,2,4 oxadiazol 5 yl) 6h imidazo[1,5 a][1,4]benzodiazepin 6 one; 5 benzyl 8 chloro 5,6 dihydro 6 oxo 4h imidazo[1,5 a][1,4]benzodiazepine 3 carboxylic acid ethyl ester; 8 azido 5,6 dihydro 5 methyl 6 oxo 4h imidazo[1,5 a][1,4]benzodiazepine 3 carboxylic acid ethyl ester; benzodiazepine derivative; benzodiazepine receptor; benzoxazole derivative; carbamic acid derivative; isothiocyanic acid derivative; oxazolidine derivative; unclassified drug; animal experiment; animal tissue; anticonvulsant activity; article; chemical modification; drug receptor binding; drug synthesis; hydrophobicity; ligand binding; male; mouse; nonhuman; priority journal; rat; receptor affinity; structure activity relation; Animal; Benzodiazepinones; Binding Sites; Cell Membrane; Cerebellum; Cerebral Cortex; Comparative Study; Crystallization; Diazepam; Male; Mice; Models, Molecular; Molecular Structure; Receptors, GABA-A; Structure-Activity Relationship; Support, U.S. Gov't, P.H.S.; X-Ray Diffraction