Axial chirality and affinity at the GABAA receptor of triazolobenzodiazepines. (15th June 2022)

• Record Type: Journal Article
• Authors: Tanaka, Ryoko; Makino, Kosho; Tabata, Hidetsugu; Oshitari, Tetsuta; Natsugari, Hideaki; Takahashi, Hideyo
• Is Part Of: Bioorganic & medicinal chemistry. Volume 64(2022)
• Publication Date: 2022-06-15
• Subjects: Axial chirality -- Atropisomer -- Benzodiazepine -- Triazolobenzodiazepine -- GABAA receptor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116758
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Triazolobenzodiazepines substituted with a methyl group at the C 1- and C 10-positions and chloro group at C 2′ of pendant-phenyl were prepared and their physicochemical properties were investigated. The atropisomers of 1, 10-disubstituted triazolobenzodiazepines, 1d and 1f, were isolated as (a 1 R, a 2 S ) and (a 1 S, a 2 R ) isomers. Their absolute configurations were determined on the basis of CD spectra in comparison with those of stereochemically defined 9-methyl-1, 4-benzodiazepin-2-ones. Examination of the affinity at the human GABAA receptors revealed that each (a 1 R, a 2 S ) isomer of 1d and 1f possessed higher activity than its antipode (a 1 S, a 2 R ) isomer. It was also found that 1a, which behaves achirally due to the rapid conformational change, had the highest GABAA affinity, equal to that of triazolam. Considering that each eutomer of 1d and 1f is (a 1 R, a 2 S ), the conformation of 1a at the binding site of the GABAA receptor is expected to be (a 1 R, a 2 S ).