BACKGROUND AND PURPOSE:

Cannabinoid 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 cannabinoid 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. Motility of the small and large intestine was assessed in vivo under normal conditions and after acute stress. Brain penetration of AM841 was also determined.

KEY RESULTS:

AM841 behaves as an irreversible cannabinoid (CB)1 receptor agonist in vitro. AM841 potently reduces GI motility through an action on CB1 receptors in the small (EC50 0.004 mg/kg) and large (EC50 0.03 mg/kg) intestine under physiological conditions. AM841 is even more potent under conditions of acute stress, and was shown to normalize accelerated GI motility under these conditions. This compound behaves 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 possess remarkable potency represents a new class of potential therapeutic agents for the treatment of functional GI disorders.
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