Flavonoids and Biflavonoids of Amentoflavone Class as Potential Psychoactive Drug Leads

Abstract

Aims: There are several reported interactions between amentoflavone and CNS receptors especially GABA receptors and also reported interaction between flavonoids and opioid receptors. The current study determines other related compounds of amentoflavone, hinokiflavone and other flavonoid monomers with potential CNS activity. Study Design: Natural and semisynthetic derivative of biflavonoids of amentoflavone and hinokiflavone class and several flavonoid monomers were screened for their binding ability to CNS receptor and neurotransmitter transporters using the Psychoactive Drug Screening Program (PDSP) University of North Carolina at Chapel Hill. Methodology: Natural and semisynthetic flavonoid derivatives were subjected to binding assays with 44 receptors and transporters. Only compounds showing ≥50% binding inhibition in the primary assay were subjected to secondary binding assay. Results: In the secondary binding assay; significant binding with rat benzodiazepine receptor, dopamine transporter, GABAA, norepinephrine transporter and Sigma 2 receptors were observed. (+) Catechin and sakurantin showed significant binding with dopamine transporter (Ki= 1 and 1.6 nM respectively) compared to the positive control (GBR 12909; Ki= 1 nM) in addition to the biflavonoid 7,7″,4‴-trimethyl-2,3-dihydroamentoflavone (16517) which showed activity at Ki= 172 nM and we present the first report of its 13C NMR data. Semi synthesis afforded the new derivative 7,7″,4‴-trimethyldihydrohinokiflavone but it was inactive towards the screened receptors and neurotransmitter transporters. Conclusion: Studying the structure-activity relationship revealed that methylation of amentoflavone decreased their ability to bind with rBZP, GABAA receptor and NET except for 7,7″,4‴-trimethyl-2,3-dihydroamentoflavone which was the most active among biflavonoids toward DAT. On the other hand, methylation of naringenin created new binding capability of sakurantin. Configurations of the chiral center at C-3 and hydroxylation pattern at ring B in flavan-3-ols greatly affect binding with dopamine transporter. Dihydrohinokiflavone and its trimethyl derivatives were completely inactive. Our study reveals new biological activity of some common flavonoids that may be promising drugs leads.