title: AM841, a covalent cannabinoid ligand, powerfully slows gastrointestinal motility in normal and stressed mice in a peripherally restricted manner.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors.forename: C M
authors.initials: CM
authors.lastname: Keenan
authors.forename: M A
authors.initials: MA
authors.lastname: Storr
authors.forename: G A
authors.initials: GA
authors.lastname: Thakur
authors.forename: J T
authors.initials: JT
authors.lastname: Wood
authors.forename: J
authors.initials: J
authors.lastname: Wager-Miller
authors.forename: A
authors.initials: A
authors.lastname: Straiker
authors.forename: M R
authors.initials: MR
authors.lastname: Eno
authors.forename: S P
authors.initials: SP
authors.lastname: Nikas
authors.forename: M
authors.initials: M
authors.lastname: Bashashati
authors.forename: H
authors.initials: H
authors.lastname: Hu
authors.forename: K
authors.initials: K
authors.lastname: Mackie
authors.forename: A
authors.initials: A
authors.lastname: Makriyannis
authors.forename: K A
authors.initials: KA
authors.lastname: Sharkey
mesh_terms: D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D056651:CA2 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D017615:Enteric Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007035:Hypothermia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000294:innervation; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors
chemical_list: C507046:7'-Isothiocyanato-11-hydroxy-1',1'-dimethylheptylhexahydrocannabinol; D063386:Cannabinoid Receptor Agonists; C571431:Cnr2 protein, mouse; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013759:Dronabinol