AM841, a covalent cannabinoid ligand,powerfully slows gastrointestinal motility in normal and stressed mice in a peripherally restricted manner

Background and Purpose

Cannabinoid (CB) ligands have been demonstrated to have utility as novel therapeutic agents for the treatment of pain, metabolic conditions and gastrointestinal (GI) disorders. However, many of these ligands are centrally active, which limits their usefulness. Here, we examine a unique novel covalent CB receptor ligand, AM841, to assess its potential for use in physiological and pathophysiological in vivo studies.

Experimental Approach

The covalent nature of AM841 was determined in vitro using electrophysiological and receptor internalization studies on isolated cultured hippocampal neurons. Mouse models were used for behavioural analysis of analgesia, hypothermia and hypolocomotion. The motility of the small and large intestine was assessed in vivo under normal conditions and after acute stress. The brain penetration of AM841 was also determined.

Key Results

AM841 behaved as an irreversible CB₁ receptor agonist in vitro. AM841 potently reduced GI motility through an action on CB₁ receptors in the small and large intestine under physiological conditions. AM841 was even more potent under conditions of acute stress and was shown to normalize accelerated GI motility under these conditions. This compound behaved as a peripherally restricted ligand, showing very little brain penetration and no characteristic centrally mediated CB₁ receptor-mediated effects (analgesia, hypothermia or hypolocomotion).

Conclusions and Implications

AM841, a novel peripherally restricted covalent CB₁ receptor ligand that was shown to be remarkably potent, represents a new class of potential therapeutic agents for the treatment of functional GI disorders.