Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins

The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (I-GABA) by a selection of 18 coumarin derivatives on recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC50 = 14 +/- 1 mu M) and oxypeucedanin (EC50 = 25 +/- 8 mu M) displayed the highest efficiency with I-GABA potentiation of 116 +/- 4% and 547 +/- 56%, respectively. I-GABA enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 mu M) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish I-GABA modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin comprising three hydrophobic and one aromatic feature -identified 6 out of 7 actives as hits. In summary, (oxy-) prenylated coumarin derivatives from natural origin represent new GABA(A) receptor modulators. (C) 2011 Elsevier B. V. All rights reserved.