Peripherally restricted CB1 receptor blockers

Bioorg Med Chem Lett. 2013 Sep 1;23(17):4751-60. doi: 10.1016/j.bmcl.2013.06.066. Epub 2013 Jul 4.


Antagonists (inverse agonists) of the cannabinoid-1 (CB1) receptor showed promise as new therapies for controlling obesity and related metabolic function/liver disease. These agents, representing diverse chemical series, shared the property of brain penetration due to the initial belief that therapeutic benefit was mainly based on brain receptor interaction. However, undesirable CNS-based side effects of the only marketed agent in this class, rimonabant, led to its removal, and termination of the development of other clinical candidates soon followed. Re-evaluation of this approach has focused on neutral or peripherally restricted (PR) antagonists. Supporting these strategies, pharmacological evidence indicates most if not all of the properties of globally acting agents may be captured by molecules with little brain presence. Methodology that can be used to eliminate BBB penetration and the means (in vitro assays, tissue distribution and receptor occupancy determinations, behavioral paradigms) to identify potential agents with little brain presence is discussed. Focus will be on the pharmacology supporting the contention that reported agents are truly peripherally restricted. Notable examples of these types of compounds are: TM38837 (structure not disclosed); AM6545 (8); JD5037 (15b); RTI-12 (19).

Keywords: AM6545; CB1-antagonist; Cannabinoid receptor blocker; Diabetes; Inverse agonist; JD5037; Liver diseases; Metabolic disorders; Obesity; Peripherally restricted; Rimonabant; Silent antagonist.

Publication types

  • Review

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Cocaine / analogs & derivatives
  • Cocaine / chemistry
  • Cocaine / pharmacology
  • Cocaine / therapeutic use
  • Drug Discovery / methods*
  • Humans
  • Liver Diseases / drug therapy*
  • Liver Diseases / metabolism
  • Metabolic Diseases / drug therapy*
  • Metabolic Diseases / metabolism
  • Morpholines / chemistry
  • Morpholines / pharmacology
  • Morpholines / therapeutic use
  • Obesity / drug therapy*
  • Obesity / metabolism
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
  • Receptor, Cannabinoid, CB1 / metabolism
  • Rimonabant
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use


  • AM6545
  • Morpholines
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Sulfonamides
  • 3-(4-iodophenyl)tropan-2beta-carboxylic acid phenyl ester
  • JD5037
  • Cocaine
  • Rimonabant