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AM 841, a covalent cannabinoid ligand, powerfully slows gastrointestinal motility in normal and stressed mice in a peripherally restricted manner
Author(s) -
Keenan C M,
Storr M A,
Thakur G A,
Wood J T,
WagerMiller J,
Straiker A,
Eno M R,
Nikas S P,
Bashashati M,
Hu H,
Mackie K,
Makriyannis A,
Sharkey K A
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13069
Subject(s) - cannabinoid , cannabinoid receptor , receptor , pharmacology , in vivo , agonist , motility , ligand (biochemistry) , chemistry , biology , neuroscience , biochemistry , microbiology and biotechnology
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, AM 841, to assess its potential for use in physiological and pathophysiological in vivo studies. Experimental Approach The covalent nature of AM 841 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 AM 841 was also determined. Key Results AM 841 behaved as an irreversible CB 1 receptor agonist in vitro . AM 841 potently reduced GI motility through an action on CB 1 receptors in the small and large intestine under physiological conditions. AM 841 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 CB 1 receptor‐mediated effects (analgesia, hypothermia or hypolocomotion). Conclusions and Implications AM 841, a novel peripherally restricted covalent CB 1 receptor ligand that was shown to be remarkably potent, represents a new class of potential therapeutic agents for the treatment of functional GI disorders.