Axial chirality and affinity at the GABAA receptor of triazolobenzodiazepines

Bioorganic & Medicinal Chemistry
2022.0

Abstract

Triazolobenzodiazepines substituted with a methyl group at the C1- and C10-positions and chloro group at C2' 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<sup>1</sup>R, a<sup>2</sup>S) and (a<sup>1</sup>S, a<sup>2</sup>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 GABA<sub>A</sub> receptors revealed that each (a<sup>1</sup>R, a<sup>2</sup>S) isomer of 1d and 1f possessed higher activity than its antipode (a<sup>1</sup>S, a<sup>2</sup>R) isomer. It was also found that 1a, which behaves achirally due to the rapid conformational change, had the highest GABA<sub>A</sub> affinity, equal to that of triazolam. Considering that each eutomer of 1d and 1f is (a<sup>1</sup>R, a<sup>2</sup>S), the conformation of 1a at the binding site of the GABA<sub>A</sub> receptor is expected to be (a<sup>1</sup>R, a<sup>2</sup>S).

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