Isoflavonoid derivatives from Adenocarpus cincinnatus as positive GABAA receptor modulators

GABA_A receptors are the major inhibitory receptors in the CNS, and the target for benzodiazepines, barbiturates, and various other CNS depressants. Such drugs, however, lack selectivity for different GABA_A receptor subtypes and thus, the pharmacological treatments of anxiety, epilepsy, insomnia, and mood disorders are accompanied by serious side effects. Consequently, the search for selective modulators with new scaffolds is still an urgent task.

In a search for new natural product-derived GABA_A receptor modulators, we screened a library of 880 plant and fungal extracts by means of a two-microelectrode voltage clamp assay, with Xenopus laevis oocytes expressing recombinant GABA_A receptors of the subtype α₁β₂γ_2S. A dichloromethane extract of Adenocarpus cincinnatus roots (Fabaceae) enhanced the GABA-induced chloride current (I _GABA) by 126.5%± 25.1% at 100 µg/mL. By means of HPLC-based activity profiling, a known 8-prenylisoflavone (10) and three new structurally related cis-pterocarpans (2, 8, 14) were identified as responsible for the activity. They showed promising activity in the oocyte assay, potentiating I _GABA by 491.0% to 771.1%, and exhibiting EC₅₀ values ranging from 2.8µM to 40.7µM. Further isoflavonoid derivatives, including the known cis-pterocarpan maackiain, were isolated from the extract and tested in the oocyte assay. These compounds show lower but still interesting activities, with I _GABA enhancements ranging from 100% to 300%. This work reveals pterocarpans as a new scaffold for GABA_A receptor modulators.

Fig. 1