title: Axial chirality and affinity at the GABA(A) receptor of pyrimido[1,2-a][1,4]benzodiazepines and related compounds.
abstract: The pyrimido[1,2-a][1,4]benzodiazepines (1a-c) and the 8-membered analogues (diazocines 2a and 2b) were separated into their atropisomers with HPLC on a chiral column. High stereochemical stability was observed in the atropisomer of the 8-membered derivatives (2a and 2b), and the 1,4-benzodiazepine (1c) with 2'-chloro at the pendant phenyl showed a lower energy barrier for the conversion between the atropisomers compared with that with the unsubstituted pendant phenyl (1a). The aR isomer of 1a-c was revealed to be the eutomer in GABA(A) receptor binding, and the eutomer 1c-R showed extremely potent activity with an IC(50) value of 1.5 nM.
authors.affiliation: Graduate School of Pharmaceutical Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Shoukou
authors.initials: S
authors.lastname: Lee
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kamide
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Tabata
authors.forename: Hideyo
authors.initials: H
authors.lastname: Takahashi
authors.forename: Motoo
authors.initials: M
authors.lastname: Shiro
authors.forename: Hideaki
authors.initials: H
authors.lastname: Natsugari
mesh_terms: D001569:Benzodiazepines / Q000737:chemistry* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000737:chemistry* / Q000378:metabolism
chemical_list: D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid