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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

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Abstract

Rationale

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.

Objective

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.

Materials and methods

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.

Results

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.

Conclusions

Dual FAAH and MAGL inhibition with AM4302 may be an especially effective treatment for the very difficult to treat symptom of anticipatory nausea.

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Acknowledgments

This research was supported by a grant from the Natural Sciences and Engineering Research Council (92056) to LAP, Canadian Institute of Health Research (137122) to LAP, and National Institute of Health to AM and MAK Scientific LLS (2R44DA023737) to S0A.

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Authors and Affiliations

  1. Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G2W1, Canada

    Linda A. Parker, Cheryl L. Limebeer, Erin M. Rock, Martin A. Sticht, Jordan Ward & Greig Turvey

  2. Center for Drug Discovery, Northeastern University, Boston, MA, USA

    JodiAnne T. Wood & Alexandros Makriyannis

  3. Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA, USA

    Othman Benchama, Girija Rajarshi, Shakiru O. Alapafuja & Alexandros Makriyannis

  4. MAK Scientific LLC, Northeastern University, 432 Mugar Building, Boston, MA, USA

    Alexandros Makriyannis

Authors
  1. Linda A. Parker
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  2. Cheryl L. Limebeer
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  3. Erin M. Rock
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  4. Martin A. Sticht
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  5. Jordan Ward
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  6. Greig Turvey
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  7. Othman Benchama
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  9. JodiAnne T. Wood
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  10. Shakiru O. Alapafuja
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  11. Alexandros Makriyannis
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Correspondence to Linda A. Parker.

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Parker, L.A., Limebeer, C.L., Rock, E.M. et al. 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. Psychopharmacology 233, 2265–2275 (2016). https://doi.org/10.1007/s00213-016-4277-y

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  • DOI: https://doi.org/10.1007/s00213-016-4277-y

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