Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice

Pharmacol Res. 2014 Feb;80:52-65. doi: 10.1016/j.phrs.2013.12.010. Epub 2014 Jan 8.

Abstract

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.

Keywords: (+)-R-WIN 55,212-2 (PubChem CID: 5311501); 2-Arachidonoylglycerol (PubChem CID: 5282280); Anandamide (PubChem CID: 5281969); Anandamide uptake; Cannabimimetic; Endocannabinoid system; Endocannabinoid transport inhibition; Guineensine; Guineensine (PubChem CID: 6442405); Haloperidol (PubChem CID: 3559); JZL184 (PubChem CID: 25021165); OMDM-2 (PubChem CID: 57347656); Rimonabant (PubChem CID: 104850); UCM707 (PubChem CID: 53394011); URB597 (PubChem CID: 1383884).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkenes / administration & dosage
  • Alkenes / chemistry
  • Alkenes / pharmacology*
  • Amidohydrolases / metabolism
  • Analgesics / administration & dosage
  • Analgesics / pharmacology*
  • Animals
  • Arachidonic Acids / metabolism*
  • Biological Transport / drug effects
  • Brain / drug effects
  • Brain / enzymology
  • Brain / metabolism
  • Cannabinoid Receptor Antagonists / pharmacology
  • Catalepsy / chemically induced
  • Dose-Response Relationship, Drug
  • Endocannabinoids / metabolism*
  • Fatty Acid-Binding Proteins
  • Glycerides / metabolism
  • Heterocyclic Compounds, 2-Ring / administration & dosage
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • Hypothermia / chemically induced
  • Locomotion / drug effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Monoacylglycerol Lipases / metabolism
  • Neoplasm Proteins
  • Piper / chemistry
  • Piperidines / pharmacology
  • Polyunsaturated Alkamides / metabolism*
  • Pyrazoles / pharmacology
  • Receptors, Cannabinoid / metabolism
  • Rimonabant
  • Serine Endopeptidases
  • Structure-Activity Relationship
  • U937 Cells

Substances

  • Alkenes
  • Analgesics
  • Arachidonic Acids
  • Cannabinoid Receptor Antagonists
  • Endocannabinoids
  • Fabp5 protein, mouse
  • Fatty Acid-Binding Proteins
  • Glycerides
  • Heterocyclic Compounds, 2-Ring
  • Neoplasm Proteins
  • Piperidines
  • Polyunsaturated Alkamides
  • Pyrazoles
  • Receptors, Cannabinoid
  • guineensine
  • glyceryl 2-arachidonate
  • Monoacylglycerol Lipases
  • Serhl protein, mouse
  • Serine Endopeptidases
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • Rimonabant
  • anandamide