Piperanine and piperine

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 microg/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-based 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 EC(50) of 52.4 +/- 9.4 microM. 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 microM). These data show that piperine (5) represents a new scaffold of positive allosteric GABA(A) receptor modulators targeting a benzodiazepine-independent binding site.

Topics: Alkaloids; Animals; Benzodiazepines; Benzodioxoles; Binding Sites; Chloride Channels; Chromatography, High Pressure Liquid; Female; Flumazenil; Fruit; GABA Modulators; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Oocytes; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Receptors, GABA-A; Xenopus laevis

A series of natural and synthetic piperine amides were evaluated for activity on the human TRPV1 expressed in HEK293 cells. The agonistic effect of piperine amides was mainly dependent on the length of the carbon chain. Structural changes of double bonds and stereochemistry in the aliphatic chain of these compounds did not change their potency or efficacy, indicating that increased rigidity or planarity of the piperine structure does not affect the activity. The opening of the methylenedioxy ring or changes in the heterocyclic ring of the piperine molecule reduced or abolished activity. Furthermore, inactive compounds did not display functional antagonistic activity.

Topics: Alkaloids; Amides; Benzodioxoles; Capsaicin; Cell Line; Dose-Response Relationship, Drug; Humans; Molecular Structure; Piperidines; Polyunsaturated Alkamides; Spectrometry, Fluorescence; TRPV Cation Channels

The methanolic extract from the fruit of Piper chaba (Piperaceae) was found to have a hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. From the ethyl acetate-soluble fraction, a new amide constituent named piperchabamide E together with twenty known amide constituents (e.g., piperine, piperchabamides A-D, and piperanine) and two aromatic constituents were isolated as the hepatoprotective constituents. With regard to structure-activity relationships, the amide moiety and the 1,9-decadiene structure between the benzene ring and amide moiety were suggested to be important for strong inhibition of D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes. Furthermore, a principal amide constituent, piperine, dose-dependently inhibited increase in serum GPT and GOT levels at doses of 2.5-10 mg/kg (p.o.) in D-GalN/LPS-treated mice, and this inhibitory effect was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.

Topics: Alanine Transaminase; Alkaloids; Amides; Animals; Aspartate Aminotransferases; Benzodioxoles; Cell Death; Chromatography, High Pressure Liquid; Fruit; Galactosamine; Hepatocytes; Lipopolysaccharides; Liver; Liver Diseases; Male; Mice; Mice, Mutant Strains; Molecular Structure; Piperaceae; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Structure-Activity Relationship; Tumor Necrosis Factor-alpha