Drechmerin H, a novel 1(2), 2(18)-diseco indole diterpenoid from the fungus Drechmeria sp. as a natural agonist of human pregnane X receptor.

A novel 1(2), 2(18)-diseco indole diterpenoid, drechmerin H (1), was isolated from the fermentation broth of Drechmeria sp. together with a new indole diterpenoid, 2'-epi terpendole A (3), and a known analogue, terpendole A (2). Their structures were determined by HRESIMS, 1D and 2D NMR, ECD, and X-ray single crystal diffraction analyses as well as quantum chemical calculation. The abosulte configuration of terpendole A (2) was determined for the first time. Compound 1 displayed the significant agonistic effect on pregnane X receptor (PXR) with EC50 value of 134.91 ±â€¯2.01 nM, and its interaction with PXR was investigated by molecular docking. Meantime, a plausible biosynthetic pathway for compounds 1-3 is also discussed in the present work.

Isolation and identification of two new sargentodoxosides from Sargentodoxa cuneata and their agonistic effects against FXR.

Sargentodoxa cuneata (Oliv.) Rehd. et Wils is a traditional Chinese medicine to treat acute appendicitis, rheumarthritis, abdominal pain, and painful menstruation for a long history. The investigation of S. cuneata led to the isolation and identification of twenty-three secondary metabolites, including two new compounds, sargentodoxosides A (1) and B (2), and twenty-one known ones (3-23). Their structural characterization was conducted by HRESIMS, 1 D and 2 D NMR spectra. All the isolated compounds were assayed for their agonistic activities against the farnesoid X receptor (FXR). Nine of the isolated compounds displayed significant agonistic effects against FXR at 0.1 µM, suggesting that they could be served as potential agents for the development of FXR agonists.

Electrophysiological characterization of a novel AMPA receptor potentiator, TAK-137, in rat hippocampal neurons.

We have recently discovered an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) potentiator TAK-137, 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4] thiadiazine 2,2-dioxide with little agonistic effect. Under preclinical evaluation, TAK-137 demonstrated potent pro-cognitive effects with lower risks of seizure and bell-shaped dose response than LY451646, a potent AMPA-R potentiator, in rodents and monkeys. In this study, using rat primary cultured hippocampal neurons we explored the electrophysiological characterization of TAK-137 on native AMPA-Rs. TAK-137 dose-dependently enhanced AMPA-induced inward currents; its potency in the presence of AMPA was comparable to that of LY451646. The inward currents enhanced by TAK-137 were almost completely inhibited by GYKI53655, a selective AMPA-R blocker. Moreover, TAK-137 did not affect N-methyl-D-aspartate (NMDA)-activated inward currents, which suggests the AMPA-R-selective activation by TAK-137. In the absence of AMPA-R agonist, LY451646 at 30 µM induced slowly developing large inward currents, whereas TAK-137 at 30 µM exhibited a slight impact on baseline holding currents, further supporting the lower agonistic properties of TAK-137 than LY451646. Similar to LY451646, TAK-137 also increased the potency and binding affinity of AMPA for AMPA-Rs. These results indicate that TAK-137 is a highly potent and selective potentiator with little agonistic effect against native AMPA-Rs. Much greater agonistic effects of LY451646 than of TAK-137 may contribute to the increased risks of seizure and bell-shaped dose response in vivo.