retrofractamide-a and guineensine

FAAH-like anandamide transporter (FLAT) regulates anandamide transport for hydrolysis and may be an attractive drug target for pain regulation. We aimed to discover potential FLAT antagonists from traditional Chinese medicine (TCM) using virtual screening, ligand-based drug design and molecular dynamics simulation (MD). Guineensine and Retrofractamide A exhibited high Dock Scores in FLAT. Consensus from multiple linear regression (MLR; R(2) = 08973) and support vector machine (SVM; R(2) = 0.7988) showed similar bioactivities for Guineensine and the FAAH-1 inhibitor (9Z)-1-(5-pyridin-2-yl-1,3,4-oxadiazol-2-yl)octadec-9-en-1-one. Contour of Guineensine to CoMFA and CoMSIA features also imply bioactivity. MD revealed shake or vibration in the secondary structure of FLAT complexed with Guineensine and (9Z)-1-(5-pyridin-2-yl-1,3,4-oxadiazol-2-yl)octadec-9-en-1-one. Ligand movement might contribute to protein changes leading to vibration patterns. Violent vibrations leading to an overall decrease in FLAT function could be the underlying mechanism for Guineensine. Here we suggest Guineensine as a drug-like compound with potential application in relieving neuropathic pain by inhibiting FLAT.

Topics: Alkenes; Amides; Amino Acid Sequence; Animals; Benzodioxoles; Binding Sites; Drug Design; Fatty Acid-Binding Proteins; Heterocyclic Compounds, 2-Ring; Humans; Linear Models; Medicine, Chinese Traditional; Molecular Docking Simulation; Molecular Sequence Data; Neuralgia; Protein Structure, Secondary; Protein Structure, Tertiary; Quantitative Structure-Activity Relationship; Rats; Sequence Alignment; Support Vector Machine

The insecticidal activity of Piper nigrum fruit-derived piperidine alkaloid (piperine) and N-isobutylamide alkaloids (pellitorine, guineensine, pipercide and retrofractamide A) against female adults of Culex pipiens pallens and Aedes aegypti was examined. On the basis of 24-h LD(50) values, the compound most toxic to female C. pipiens pallens was pellitorine (0.4 µg/♀) followed by guineensine (1.9 µg/♀), retrofractamide A (2.4 µg/♀) and pipercide (3.2 µg/♀). LD(50) value of chlorpyrifos was 0.03 µg/♀. Against female A. aegypti, the insecticidal activity was more pronounced in pellitorine (0.17 µg/♀) than in retrofractamide A (1.5 µg/♀), guineensine (1.7 µg/♀), and pipercide (2.0 µg/♀). LD(50) value of chlorpyrifos was 0.0014 µg/♀.

Topics: Aedes; Alkaloids; Alkenes; Amides; Animals; Benzodioxoles; Culex; Fatty Acids, Unsaturated; Female; Heterocyclic Compounds, 2-Ring; Insecticides; Male; Piper nigrum; Piperidines; Polyunsaturated Alkamides

A total synthesis of guineensine, a secondary metabolite of the Piperaceae family, has been executed in 12 steps with an overall yield of 27%. Key steps in the synthesis featured novel application of a Julia-Kocienski olefination reaction which effectively constructed alkenamide skeleton. This contributes a unique approach to the synthesis of the piperamide alkaloids.

Topics: Alkenes; Amides; Benzodioxoles; Heterocyclic Compounds, 2-Ring; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Piperaceae