Cornepalenins A–D, picrotoxane-type sesquiterpenes from the flowers of Coriaria nepalensis associated with modulation of GABAB receptor–related signaling

Three new picrotoxane-type sesquiterpenes (PSTs) cornepalenins A–C ( 1 – 3 ), along with eight known analogues ( 4 – 11 ), were isolated and identified from the flowers of Coriaria nepalensis . In addition, the spectroscopic data and absolute configurations of the known compound cornepalenin D ( 4 ) are reported for the first time. Biological evaluation results showed that multiple compounds exhibited certain inhibitory effects on GABA B receptor–mediated signaling pathways in both primary cerebellar granule neurons and GABA B receptor–overexpressing HEK 293 T cells. Among them, compound 6 displayed relatively stronger inhibitory activity under stimulation with GABA and baclofen, and was more potent than the positive control CGP54626. The IC 50 value of compound 6 was 1.41 ± 0.86 μM under GABA stimulation and 1.45 ± 0.55 μM under baclofen stimulation. In addition, mechanistic studies indicated that this compound suppressed the phosphorylation of ERK1/2. Collectively, this study demonstrates that PSTs can modulate GABA B receptor–related signaling pathways and provides experimental evidence for their further investigation in central nervous system–related disorders.