title: Effects of flavone 6-substitutions on GABAA receptors efficacy.
abstract: Flavones have been studied for their activities via benzodiazepine site on the type-A γ-aminobutyric acid (GABA(A)) receptors, for which knowledge on structure-efficacy relationships has been rather limited in comparison to that on structure-affinity relationships. The present study focused on flavone 6-substitution, implied in previous studies being relevant to efficacy. Structure analogs, each varying only at position 6, were compared, including 6-fluoroflavone, 6-chloroflavone, 6-bromoflavone, and 2'-hydroxyflavone analyzed in the present study, as well as 6,2'-dihydroxyflavone reported earlier. Radio-ligand binding assays, whole-cell patch-clamp, and mouse behavioral experiments were performed. In consistent with a previous report, the present whole-cell patch-clamp and animal behavior experiments demonstrated 6-bromoflavone to be a positive modulator at GABA(A) receptors acting through flumazenil-sensitive high-affinity benzodiazepine site. In contrast, the other two 6-haloflavones were both neutralizing modulators. In vitro electrophysiological and in vivo animal experiments showed that 2'-hydroxyflavone was a neutralizing modulator, different in efficacy from its structural analog, 6,2'-dihydroxyflavone, a negative modulator of GABA(A) receptors. The fact that flavone analogs differing only at position 6 showed drastically different pharmacological properties clearly points to 6-substitution being an important determinant of efficacy. The results suggest that a large width of the first atom on the 6-substituent favors a high binding affinity of the 6-substituted flavone, whereas a large overall volume of the 6-substituent favors positive modulator activity, which could be modified by, e.g., 2'-hydroxyl substitution. These findings have contributed to the understanding of quantitative structure-efficacy relationships for flavones acting at GABA(A) receptors, and hence facilitation of flavone-based drug development.
authors.affiliation: Division of Life Science and Applied Genomics Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Lihuan
authors.initials: L
authors.lastname: Ren
authors.forename: Wing Man
authors.initials: WM
authors.lastname: Chan
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Xu
authors.forename: Cunyou
authors.initials: C
authors.lastname: Zhao
authors.forename: Wai Kin
authors.initials: WK
authors.lastname: Mat
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Chai
authors.forename: J Tze-Fei
authors.initials: JT
authors.lastname: Wong
authors.forename: Shui Ying
authors.initials: SY
authors.lastname: Tsang
authors.forename: Hong
authors.initials: H
authors.lastname: Xue
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000737:chemistry* / Q000494:pharmacology*; D006219:Halogens / Q000737:chemistry; D006878:Hydroxides / Q000737:chemistry; D008024:Ligands; D008297:Male; D051379:Mice; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D047309:Flavones; D006219:Halogens; D006878:Hydroxides; D008024:Ligands; D011963:Receptors, GABA-A; C031356:hydroxide ion