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

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Abstract
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 covalentCBreceptor ligand,AM841, to assess its potential for use in physiological and pathophysiologicalin vivostudies.Experimental Approach: The covalent nature ofAM841 was determinedin vitrousing 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 assessedin vivounder normal conditions and after acute stress. The brain penetration ofAM841 was also determined.Key Results: AM841 behaved as an irreversibleCB1receptor agonistin vitro.AM841 potently reducedGImotility through an action onCB1receptors in the small and large intestine under physiological conditions.AM841 was even more potent under conditions of acute stress and was shown to normalize acceleratedGImotility under these conditions. This compound behaved as a peripherally restricted ligand, showing very little brain penetration and no characteristic centrally mediatedCB1receptor‐mediated effects (analgesia, hypothermia or hypolocomotion).Conclusions and Implications: AM841, a novel peripherally restricted covalentCB1receptor ligand that was shown to be remarkably potent, represents a new class of potential therapeutic agents for the treatment of functionalGIdisorders.
Funding Information
  • National Institutes of Health
  • Canadian Institutes of Health Research (MOP 38185)

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