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.
Ananthan
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Organic Chemistry Department, Southern Research Institute, Birmingham, Alabama 35255.
Clayton
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SD
Ealick
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Wong
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Evoniuk
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Skolnick
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P
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