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Anandamide and 2-arachidonoylglycerol: the cyclooxygenase connection

Research project Why do we have several different pathways to metabolize anandamide and 2-arachidonoylglycerol? My research group is investigating this question at the level of basic science.

Anandamide and 2-arachidonoylglycerol are two endogenous lipid signalling molecules responsible for effects as diverse as control of appetite, pain and cancer. As with all signalling molecules, the body has effective metabolic pathways for their synthesis and removal. With respect to the latter, they are metabolised primarily by hydrolysis to their corresponding long-chain fatty acids. However, they are also substrates for cyclooxygenase-2 to produce compounds that themselves are biologically active. The research project investigates the importance of these pathways, and how they can selectively be targeted.

Head of project

Project overview

Project period

2014-12-02 2018-12-31

Funding

The Swedish Research Council, 2003-2018: SEK 12,648,000
The Swedish Cancer Society, 2011-2013: SEK 1,500,000

Research subject

Pharmaceutical science

Project description

Anandamide and 2-arachidonoylglycerol are two endogenous lipid signalling molecules responsible for effects as diverse as control of appetite, pain and cancer. As with all signalling molecules, the body has effective metabolic pathways for their synthesis and removal. With respect to the latter, they are metabolised primarily by hydrolysis to their corresponding long-chain fatty acids. However, they are also substrates for cyclooxygenase-2 to produce compounds that themselves are biologically active.

Our research initiated in 1995 and supported by the Swedish Research Council, is primarily focused on exploring the roles these lipids play in health and in diseases such as pain and cancer, and in understanding (and by extension exploiting) the mechanisms that are involved in the metabolism of AEA and its related lipids such as palmitoylethanolamide.

Some of our research findings
Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen work by inhibiting the activity of cyclooxygenases. However, use of these drugs can result in serious gastrointestinal and cardiovascular adverse effects. In 1997, we reported that FAAH, the enzyme responsible for the hydrolysis of AEA, is inhibited by the ibuprofen at pharmacologically relevant concentrations, raising the possibility that such an effect can contribute to the mechanism of action of NSAIDs. This finding has initiated a programme, together with the medicinal chemistry group of Dr. Valentina Onnis at the University of Cagliari, to identify NSAID analogues compounds with improved FAAH inhibitory properties while retaining their profile towards cyclooxygenase, with the aim of producing novel non-steroidal anti-inflammatory drugs lacking the unwanted effects associated with the agents in current clinical use. Our latest finding is the identification of an analogue of flurbiprofen, flu-AM1 as a potentially promising compound.