Axial chirality and affinity at the GABAA receptor of triazolobenzodiazepines

Ryoko Tanaka; Kosho Makino; Hidetsugu Tabata; Tetsuta Oshitari; Hideaki Natsugari; Hideyo Takahashi

doi:10.1016/j.bmc.2022.116758

Axial chirality and affinity at the GABA_A receptor of triazolobenzodiazepines

Bioorg Med Chem. 2022 Jun 15:64:116758. doi: 10.1016/j.bmc.2022.116758. Epub 2022 Apr 18.

Authors

Ryoko Tanaka¹, Kosho Makino¹, Hidetsugu Tabata², Tetsuta Oshitari², Hideaki Natsugari³, Hideyo Takahashi⁴

Affiliations

¹ Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641Yamazaki, Noda-shi, Chiba 278-8510, Japan.
² Faculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
³ Graduate School of Pharmaceutical Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
⁴ Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641Yamazaki, Noda-shi, Chiba 278-8510, Japan. Electronic address: hide-tak@rs.tus.ac.jp.

PMID: 35472555
DOI: 10.1016/j.bmc.2022.116758

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 (a¹R, a²S) and (a¹S, a²R) 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_A receptors revealed that each (a¹R, a²S) isomer of 1d and 1f possessed higher activity than its antipode (a¹S, a²R) isomer. It was also found that 1a, which behaves achirally due to the rapid conformational change, had the highest GABA_A affinity, equal to that of triazolam. Considering that each eutomer of 1d and 1f is (a¹R, a²S), the conformation of 1a at the binding site of the GABA_A receptor is expected to be (a¹R, a²S).

Keywords: Atropisomer; Axial chirality; Benzodiazepine; GABA(A) receptor; Triazolobenzodiazepine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzodiazepines* / chemistry
Binding Sites
Humans
Isomerism
Receptors, GABA-A* / metabolism
gamma-Aminobutyric Acid

Substances

Receptors, GABA-A
Benzodiazepines
gamma-Aminobutyric Acid