Esters, retroesters, and a retroamide of palmitic acid: pool for the first selective inhibitors of N-palmitoylethanolamine-selective acid amidase

J Med Chem. 2003 Oct 9;46(21):4373-6. doi: 10.1021/jm0340795.

Abstract

Cyclohexyl hexadecanoate, hexadecyl propionate, and N-(3-hydroxypropionyl)pentadecanamide, respectively ester, retroester, and retroamide derivatives of N-palmitoylethanolamine, represent the first selective inhibitors of "N-palmitoylethanolamine hydrolase" described so far. These compounds are devoid of affinity for CB(1) and CB(2) receptors and characterized by high percentages of inhibition of N-palmitoylethanolamine-selective acid amidase (84.0, 70.5, and 76.7% inhibition at 100 microM, respectively) with much lower inhibitory effect on either fatty acid amide hydrolase or the uptake of anandamide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / pharmacology
  • Amidohydrolases / antagonists & inhibitors*
  • Animals
  • Arachidonic Acids / metabolism
  • Benzoxazines
  • Binding, Competitive / drug effects
  • Brain / drug effects
  • Brain / enzymology
  • CHO Cells
  • Calcium Channel Blockers / metabolism
  • Cricetinae
  • Cyclohexanols / metabolism
  • Endocannabinoids
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Esters / chemical synthesis
  • Esters / pharmacology
  • Humans
  • Indicators and Reagents
  • Lung / drug effects
  • Lung / enzymology
  • Morpholines / metabolism
  • Naphthalenes / metabolism
  • Palmitates / chemical synthesis*
  • Palmitates / metabolism
  • Palmitates / pharmacology*
  • Polyunsaturated Alkamides
  • Rats
  • Receptor, Cannabinoid, CB2*
  • Receptors, Cannabinoid
  • Receptors, Drug / drug effects
  • Receptors, Drug / metabolism

Substances

  • Amides
  • Arachidonic Acids
  • Benzoxazines
  • Calcium Channel Blockers
  • Cnr2 protein, rat
  • Cyclohexanols
  • Endocannabinoids
  • Enzyme Inhibitors
  • Esters
  • Indicators and Reagents
  • Morpholines
  • Naphthalenes
  • Palmitates
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB2
  • Receptors, Cannabinoid
  • Receptors, Drug
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • Amidohydrolases
  • N-palmitoylethanolamine-selective acid amidase
  • anandamide