title: A comparison of novel, selective fatty acid amide hydrolase (FAAH), monoacyglycerol lipase (MAGL) or dual FAAH/MAGL inhibitors to suppress acute and anticipatory nausea in rat models.
abstract: Drugs that block fatty acid amide hydrolase (FAAH, which elevates anandamide [AEA]) and drugs which block monoacylglycerol (MAGL, which elevates 2-arachidonyl glycerol [2-AG]) have promise in treating both acute and anticipatory nausea in human patients.
  
  
  
  This study aims to evaluate the relative effectiveness of dual MAGL/FAAH inhibition with either alone to reduce acute and anticipatory nausea in rat models.
  
  
  
  AM4302, a new dual MAGL/FAAH inhibitor, was compared with a new selective MAGL inhibitor, AM4301, and new selective FAAH inhibitor, AM4303, for their potential to reduce acute nausea (gaping in taste reactivity) and anticipatory nausea (contextually elicited conditioned gaping) in two rat models.
  
  
  
  Our in vitro studies indicate that AM4302 blocks human and rat FAAH: IC50 60 and 31 nM, respectively, with comparable potencies against human MAGL (IC50 41 nM) and rat MAGL (IC50 200 nM). AM4301 selectively blocks human and rat MAGL (IC50 8.9 and 36 nM, respectively), while AM4303 selectively inhibits human and rat FAAH (IC50 2 and 1.9 nM), respectively. Our in vivo studies show that the MAGL inhibitor, AM4301, suppressed acute nausea in a CB1-mediated manner, when delivered systemically or into the interoceptive insular cortex. Although the dual FAAH/MAGL inhibitor, AM4302, was equally effective as the FAAH inhibitor or MAGL inhibitor in reducing acute nausea, it was more effective than both in suppressing anticipatory nausea.
  
  
  
  Dual FAAH and MAGL inhibition with AM4302 may be an especially effective treatment for the very difficult to treat symptom of anticipatory nausea.
authors.affiliation: Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G2W1, Canada. parkerl@uoguelph.ca.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Parker
authors.affiliation: Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G2W1, Canada.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Limebeer
authors.affiliation: Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G2W1, Canada.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Rock
authors.affiliation: Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G2W1, Canada.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Sticht
authors.affiliation: Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G2W1, Canada.
authors.forename: Jordan
authors.initials: J
authors.lastname: Ward
authors.affiliation: Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G2W1, Canada.
authors.forename: Greig
authors.initials: G
authors.lastname: Turvey
authors.affiliation: Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
authors.forename: Othman
authors.initials: O
authors.lastname: Benchama
authors.affiliation: Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
authors.forename: Girija
authors.initials: G
authors.lastname: Rajarshi
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.
authors.forename: JodiAnne T
authors.initials: JT
authors.lastname: Wood
authors.affiliation: Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
authors.forename: Shakiru O
authors.initials: SO
authors.lastname: Alapafuja
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.|Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.|MAK Scientific LLC, Northeastern University, 432 Mugar Building, Boston, MA, USA.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000208:Acute Disease; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009325:Nausea / Q000188:drug therapy* / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014840:Vomiting, Anticipatory / Q000188:drug therapy* / Q000201:enzymology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D000099252:Fatty Acid Amide Hydrolases
keywords: Endocannabinoids; FAAH; MAGL; Nausea; Rat