piperidines and guineensine

High-content screening led to the identification of the N-isobutylamide guineensine from Piper nigrum as novel nanomolar inhibitor (EC50=290nM) of cellular uptake of the endocannabinoid anandamide (AEA). Noteworthy, guineensine did not inhibit endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) nor interact with cannabinoid receptors or fatty acid binding protein 5 (FABP5), a major cytoplasmic AEA carrier. Activity-based protein profiling showed no inhibition of serine hydrolases. Guineensine also inhibited the cellular uptake of 2-arachidonoylglycerol (2-AG). Preliminary structure-activity relationships between natural guineensine analogs indicate the importance of the alkyl chain length interconnecting the pharmacophoric isobutylamide and benzodioxol moieties for AEA cellular uptake inhibition. Guineensine dose-dependently induced cannabimimetic effects in BALB/c mice shown by strong catalepsy, hypothermia, reduced locomotion and analgesia. The catalepsy and analgesia were blocked by the CB1 receptor antagonist rimonabant (SR141716A). Guineensine is a novel plant natural product which specifically inhibits endocannabinoid uptake in different cell lines independent of FAAH. Its scaffold may be useful to identify yet unknown targets involved in endocannabinoid transport.

Topics: Alkenes; Amidohydrolases; Analgesics; Animals; Arachidonic Acids; Biological Transport; Brain; Cannabinoid Receptor Antagonists; Catalepsy; Dose-Response Relationship, Drug; Endocannabinoids; Fatty Acid-Binding Proteins; Glycerides; Heterocyclic Compounds, 2-Ring; Humans; Hypothermia; Locomotion; Male; Mice; Mice, Inbred BALB C; Monoacylglycerol Lipases; Neoplasm Proteins; Piper; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Serine Endopeptidases; Structure-Activity Relationship; U937 Cells

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