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.
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.
Organic Chemistry Department, Southern Research Institute, Birmingham, Alabama 35255.
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Ananthan
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Clayton
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Ealick
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Wong
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Evoniuk
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Skolnick
D000818:Animals; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003460:Crystallization; D003975:Diazepam / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D001570:Benzodiazepinones; D011963:Receptors, GABA-A; D003975:Diazepam