Metabolic Profiling of CB1 Neutral Antagonists

Herbert H. Seltzman*, Rangan Maitra, Katharine Bortoff, Jay Henson, Patricia H. Reggio, Daniel Wesley, Joseph Tam

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

13 Scopus citations

Abstract

PIMSR is among the first neutral antagonists for the CB1R and was demonstrated pharmacologically to bind to the CB1R, yet not alter calcium flux. It was further shown computationally to be able to stabilize both the active and inactive states of CB1R revealing the molecular interactions that mechanistically afford the property of neutral antagonism. PIMSR shows dramatic positive effects in reducing weight, food intake, and adiposity as well as in improving glycemic control and lipid homeostasis in high-fat diet-induced obese mice, but also shows increased ALT and liver weight as markers of liver injury with chronic administration. Further, in a separate study, 3-day administration of PIMSR in C57BL/6J mice, hepatic steatosis from an acute administration of high of ethanol was significantly reduced. Also, it partially prevented alcohol-induced increases in ALT, AST, and LDH. The differences in ALT levels in obese and nonobese mice under different test paradigms are unlikely to be due to neutral antagonism itself since other neutral antagonists (AM6545) do not exhibit liver injury. The brain levels of low micromolar would support significant brain CB1 receptor occupancy (re: Ki = 17 nM), thus potentially including both CNS and peripheral influences on the observed weight loss. Overall, these studies suggest that marked improvements in aspects of metabolic disease and alcoholic steatosis can be realized with CB1R neutral antagonists and hence warrants the exploration of further members of this class of cannabinoid ligands.

Original languageAmerican English
Title of host publicationMethods in Enzymology
PublisherAcademic Press Inc.
Pages199-215
Number of pages17
DOIs
StatePublished - 2017

Publication series

NameMethods in Enzymology
Volume593
ISSN (Print)0076-6879
ISSN (Electronic)1557-7988

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

  • Alcoholic steatosis
  • CB1R
  • Glycemic control
  • Metabolic syndrome effects
  • Modeling
  • Neutral antagonist
  • Obesity
  • PIMSR

Fingerprint

Dive into the research topics of 'Metabolic Profiling of CB1 Neutral Antagonists'. Together they form a unique fingerprint.

Cite this