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Characterization of tunable piperidine and piperazine carbamates as inhibitors of endocannabinoid hydrolases

Academic Article
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Overview

related to degree

  • Long, Jonathan, Ph.D. in Chemistry, Scripps Research 2007 - 2011
  • Li, Weiwei, Ph.D. in Chemical Biology, Scripps Research 2005 - 2010

authors

  • Long, Jonathan
  • Jin, X.
  • Adibekian, Alexander
  • Li, Weiwei
  • Cravatt, Benjamin

publication date

  • February 2010

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) are two enzymes from the serine hydrolase superfamily that degrade the endocannabinoids 2-arachidonoylglycerol and anandamide, respectively. We have recently discovered that MAGL and FAAH are both inhibited by carbamates bearing an N-piperidine/piperazine group. Piperidine/piperazine carbamates show excellent in vivo activity, raising brain endocannabinoid levels and producing CB1-dependent behavioral effects in mice, suggesting that they represent a promising class of inhibitors for studying the endogenous functions of MAGL and FAAH. Herein, we disclose a full account of the syntheses, structure-activity relationships, and inhibitory activities of piperidine/piperazine carbamates against members of the serine hydrolase family. These scaffolds can be tuned for MAGL-selective or dual MAGL-FAAH inhibition by the attachment of an appropriately substituted bisarylcarbinol or aryloxybenzyl moiety, respectively, on the piperidine/piperazine ring. Modifications to the piperidine/piperazine ring ablated inhibitory activity, suggesting a strict requirement for a six-membered ring to maintain potency.

subject areas

  • Amidohydrolases
  • Animals
  • Brain
  • Carbamates
  • In Vitro Techniques
  • Mice
  • Monoacylglycerol Lipases
  • Piperazines
  • Piperidines
  • Structure-Activity Relationship
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Identity

PubMed Central ID

  • PMC2828288

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm9016976

PubMed ID

  • 20099888
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Additional Document Info

start page

  • 1830

end page

  • 1842

volume

  • 53

issue

  • 4

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