title: Synthesis of benzo-fused benzodiazepines employed as probes of the agonist pharmacophore of benzodiazepine receptors.
abstract: The synthesis and in vitro evaluation of benzo-fused benzodiazepines 1-6 are described. These "molecular yardsticks" were employed to probe the spatial dimensions of the lipophilic pocket L2 in the benzodiazepine receptor (BzR) cleft and to determine the effect of occupation of L2 with respect to agonist activity. Of the new analogs synthesized, the 7,8-benzo-fused benzodiazepine 6 displayed moderately high affinity for the BzR (IC50 = 55 nM) and exhibited both anticonvulsant (ED50 approximately 15 mg/kg) and muscle relaxant (ED50 approximately 15 mg/kg) activity. As expected, 2 and 4 interacted with the repulsive regions of interaction, S1 and S2, and exhibited low affinities for BzR. The rigid nature of these molecular yardsticks (especially 6, Figure 7) has been employed to probe the depth of L2. Moreover, in the case of 6 full occupation of L2 has resulted in an increase in the muscle relaxant effect at the expense of the anticonvulsant/anxiolytic effect.
authors.affiliation: Department of Chemistry, University of Wisconsin-Milwaukee 53201.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: K F
authors.initials: KF
authors.lastname: Koehler
authors.forename: B
authors.initials: B
authors.lastname: Harris
authors.forename: P
authors.initials: P
authors.lastname: Skolnick
authors.forename: J M
authors.initials: JM
authors.lastname: Cook
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines