Journal
JOURNAL OF NATURAL PRODUCTS
Volume 73, Issue 2, Pages 185-191Publisher
AMER CHEMICAL SOC
DOI: 10.1021/np900656g
Keywords
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Funding
- Swiss National Science Foundation [1600-113109, 205321-116157/1]
- Steinegg-Stiftung, Herisau
- Fonds zur Forderung von Lehre und Forschung, Basel
- FWF [P19614-B11]
- Korean Government (MOEHRD) [KRF-2006-352-E00026]
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A plant extract library was screened for GABA(A) receptor activity making use of a two-microelectrode voltage clamp assay on Xenopus laevis oocytes. An ethyl acetate extract of black pepper fruits [Piper nigrum L. (Piperaceae) 100 mu g/mL] potentiated GABA-induced chloride currents through GABA(A) receptors (composed of alpha(1), beta(2), and gamma(2S) subunits) by 169.1 +/- 2.4%. With the aid of an HPLC-bsed activity profiling approach, piperine (5) was identified as the main active compound, together with 12 structurally related less active or inactive piperamides (1-4, 6-13). Identification was achieved by on-line high-resolution mass spectrometry and off-line microprobe 1D and 2D NMR spectroscopy, using only milligram amounts of extract. Compound 5 induced a maximum potentiation of the chloride currents by 301.9 +/- 26.5% with an EC50 of 52.4 +/- 9.4 mu M. A comparison of the modulatory activity of 5 and other naturally occurring piperamides enabled insights into structural features critical for GABA(A) receptor modulation. The stimulation of chloride currents through GABA(A) receptors by compound 5 was not antagonized by flumazenil (10 mu M). These data show that piperine (5) represents a new scaffold of positive allosteric GABA(A) receptor modulators targeting a benzodiazepine-independent binding site.
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