Development of antalgic agents

This research activity led to the development of potent and selective inhibitors for the enzymes FAAH and MAGL as potential antalgic agents.

Endocannabinoid metabolism is driven by two main enzymes: the fatty acid amide hydrolase (FAAH) and the monoacylglycerol lipase (MAGL). The development of selective inhibitors for FAAH and MAGL would allow the modulation of the endocannabinoid system without eliciting the side effects associated with the direct stimulation of cannabinoid receptors. Extremely potent and selective FAAH inhibitors have been developed and their antalgic potential has been demonstrated in vivo. Very recently, novel extremely potent and selective MAGL inhibitors have been also developed.

Researchers involved

• Giuseppe Campiani

This research activity led to the identification of a new class on non-nucleoside inhibitors of adenosine kinase with a pyrrolobenzoxazepine structure.

The rational design of a new series of non-nucleoside Adenosine Kinase inhibitors based on a pyrrolobenzoxazepinone scaffold allowed the identification of a putative allosteric site. This research activity may pave the way to development of potent non-nucleoside Adenosine Kinase inhibitors targeting this newly described site (identified for the first time by our research group) and devoid of the toxicities associated with nucleoside-like inhibitors.

Researchers involved

• Giuseppe Campiani

This research activity led to the identification  of potent agonists and antagonists of GluK1 receptor endowed with antalgic activity.

Kainate glutamatergic GluK1 receptor subtype agonists and antagonists have been developed as potential pain therapeutics. During this activity an in depth analysis of the developed pyrimidinedione ligands was performed by means of X-ray analysis of the ligands in complex with the receptor binding domain. This analysis furnished key details about the molecular mechanism of ligand binding to GluK1 receptor thus paving the way to the development of novel specific ligands.

Researchers involved

• Giuseppe Campiani