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The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

  • Chapter
Endocannabinoids

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 231))

Abstract

The endocannabinoids anandamide and 2-arachidonoylglycerol are metabolised by both hydrolytic enzymes (primarily fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL)) and oxygenating enzymes (e.g. cyclooxygenase-2, COX-2). In the present article, the in vivo data for compounds inhibiting endocannabinoid metabolism have been reviewed, focussing on inflammation and pain. Potential reasons for the failure of an FAAH inhibitor in a clinical trial in patients with osteoarthritic pain are discussed. It is concluded that there is a continued potential for compounds inhibiting endocannabinoid metabolism in terms of drug development, but that it is wise not to be unrealistic in terms of expectations of success.

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Notes

  1. 1.

    Phenotypical screening (here inhibition of uptake) is of course a highly valid route to drug discovery, and it has been argued that it is a more appropriate route to first-in-class drugs than a target-centric approach (Enna and Williams 2009; Swinney and Anthony 2011). Follow-up drugs tend to be discovered more frequently on the basis of target-based approaches than phenotypic assays (Swinney and Anthony 2011). If it is argued that cannabis-based medicines are first in class, the target-based approach discussed in the present article makes sense. On the other hand, if cannabinoid-based medicines do not represent the same biological realm as inhibitors of NAE and MAG metabolism, then a phenotypical approach is well warranted. Identification of uptake inhibitors with considerably improved potencies to those currently available may well lead to useful drugs. For a review on the therapeutic potential of endocannabinoid uptake inhibitors, see Di Marzo (2008).

  2. 2.

    Randomised clinical trials.

  3. 3.

    To my knowledge, the only other completed efficacy study of an FAAH inhibitor in patients with pain was a compound from Ironwood Pharmaceuticals, a single dose study in patients undergoing third molar extraction (ClinicalTrials.gov identifier NCT01107236). The outcome of this study has not been reported. However, cannabinoids are not that efficacious in acute clinical pain (Beaulieu and Ware 2007), and the compound is not mentioned as far as I can see on the Ironwood website (as of May 2014) so the auguries are not good.

Abbreviations

Δ9-THC:

Δ9-Tetrahydrocannabinol

2-AG:

2-Arachidonoylglycerol

AA-5-HT:

N-Arachidonoyl-serotonin

AEA:

Arachidonoyl ethanolamide, anandamide

(e)CB:

(Endo)cannabinoid

FAAH:

Fatty acid amide hydrolase

FABP5:

Fatty acid binding protein 5

[35S]GTPγS:

Guanosine 5′-O-(3-[35S]thio)triphosphate

IL-1ß:

Interleukin-1ß

MAG:

Monoacylglycerol

MGL:

Monoacylglycerol lipase

NAAA:

N-Acylethanolamine-hydrolyzing acid amidase

NAE:

N-Acylethanolamine

NSAID:

Nonsteroidal anti-inflammatory drug

PEA:

Palmitoylethanolamide

OEA:

Oleoylethanolamide

TRPV1:

Transient receptor potential (vanilloid) 1 ion channels

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Acknowledgements

The author thanks the Swedish Science Council (Grant no. 12158, medicine) and the Research Funds of the Medical Faculty, Umeå University, for their financial support of his research.

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  1. Department of Pharmacology and Clinical Neuroscience, Umeå University, 901 87, Umeå, Sweden

    Christopher J. Fowler

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    Roger G. Pertwee

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Fowler, C.J. (2015). The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review. In: Pertwee, R. (eds) Endocannabinoids. Handbook of Experimental Pharmacology, vol 231. Springer, Cham. https://doi.org/10.1007/978-3-319-20825-1_4

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