Syntheses of 5-thienyl and 5-furyl-substituted benzodiazepines: probes of the pharmacophore for benzodiazepine receptor agonists

Pharmacophore/Receptor Models for GABAA/BzR Subtypes (α1β3γ2, α5β3γ2, and α6β3γ2) via a Comprehensive Ligand-Mapping Approach

“…Attempts to define this activity at the pharmacophore/receptor level have been made. 52,53 Studies of the pharmacophore/receptor model via the synthesis of 1,4-benzodiazepines 70,135 and a series of β-carboline ligands 30,51 suggested that occupation of region L 3 of the receptor by a BzR ligand would lead to agonist activity. 52,67 From the CGS series it was assumed that full occupation of regions L 2 and L 3 would lead to a full agonist, while partial occupation of region L 3 would provide a partial agonist.…”

“…Chemistry. The syntheses of the ligands employed in this study have been reported elsewhere. ,,,,− ,,,,,,,,,,,,,,, …”

Benzodiazepine Receptor Ligands. 4. Synthesis and Pharmacological Evaluation of 3-Heteroaryl-8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-Oxides

“…In particular for these 3-heteroaryl derivatives , a π−π stacking interaction between the receptor and the substituent at the 3-position, thiophene, and pyrrole, which are π-excessive rings, can be hypothesized. These rings, acting as a π-electron donor, might take place in a limited size lipophilic pocket in the lipophilic region L 1 /L 2 . − From literature it is well-recognized that the sulfur atom of a thiophene ring is substantially weak to form a hydrogen bond with an active proton . Consequently the sulfur atom of compounds 13c and 13d cannot form a three-centered hydrogen bond as can the carbonyl group of the lead compound I .…”

“…These rings, acting as a π-electron donor, might take place in a limited size lipophilic pocket in the lipophilic region L 1 /L 2 . [15][16][17] From literature it is wellrecognized that the sulfur atom of a thiophene ring is substantially weak to form a hydrogen bond with an active proton. 16 Consequently the sulfur atom of compounds 13c and 13d cannot form a three-centered hydrogen bond as can the carbonyl group of the lead compound I.…”

“…[15][16][17] From literature it is wellrecognized that the sulfur atom of a thiophene ring is substantially weak to form a hydrogen bond with an active proton. 16 Consequently the sulfur atom of compounds 13c and 13d cannot form a three-centered hydrogen bond as can the carbonyl group of the lead compound I. The enhanced affinity of ligand 13c with respect to 13d might be explained by a better accommodation of the thienyl ring of the 2-isomer than the 3-isomer into the lipophilic pocket reinforcing the π-π stacking interaction.…”