Planta Med 2013; 79 - PI89
DOI: 10.1055/s-0033-1352178

Identification of dihydrostilbenes as a new scaffold for GABAA receptor modulators in Pholidota chinensis stems and roots

DC Rueda 1, A Schöffmann 2, M de Mieri 1, M Raith 1, E Jähne 1, S Hering 2, M Hamburger 1
  • 1Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland
  • 2Institute of Pharmacology and Toxicology, University of Vienna, Vienna, Austria

In a search for new natural product-derived GABAA receptor modulators, we screened a plant extract library on Xenopus laevis oocytes expressing recombinant α1β2γ2S GABAA receptors, by means of a two-microelectrode voltage clamp assay. A dichloromethane extract of stems and roots of Pholidota chinensis (Orchidaceae) enhanced the GABA-induced chloride current (I GABA) by 132.75%± 36.69% at 100 µg/mL.

By means of an HPLC-based activity profiling approach, the three structurally related stilbenoids coelonin (1), batatasin III (2), and pholidotol D (3) were identified. Dihydrostilbene 2 enhanced I GABA by 1512.19%± 176.47% at 300µM, with an EC50 of 52.51 ± 16.96µM, while compounds 1 and 3 showed much lower activity, suggesting conformational flexibility as in 2 to be crucial for receptor modulation. This was confirmed by a study on a series of 11 commercially available stilbenoids and their corresponding semisynthetic dihydro derivatives. When tested at a concentration of 100µM, dihydrostilbenes showed higher activity in the oocyte assay than their corresponding stilbenes. The dihydro derivatives of tetramethoxy piceatannol (6) and pterostilbene (11) were the most active, with modulations comparable to that of compound 2 (544.5%± 104.4% and 660.6%± 100.2%, respectively), when tested at the same concentration. Dihydrostilbenes represent a new scaffold for GABAA receptor modulators.

Fig. 1