Synthesis of new potential inhibitors for the enzyme N-Acylethanolamine Acid Amidase and investigation of substrate specificity

The enzyme N-Acylethanolamine Acid Amidase (NAAA) is a cysteine hydrolase localized in the lysomes of immune system cells. Its role is to convert the lipidic antinflammatory signal palmitoylethanolmide (PEA) in its metabolite palmitic acid. The fall of the levels of PEA, and the related increase of palmitate concentrations, leads to the activation of the immune response and the inflammatory processes. The chronical activation of this enzyme is considered to be at the base of neuroinflammation and neurodegeneration processes typical of pathologies like Alzheimer’s disease. In the first part of this project are described the synthesis of novel compounds, belonging to the nitrile chemical class, with potential activity against NAAA. The next section is focused on the study of NAAA activity using PEA derivatives of different length and functionalization to obtain and compare the main kinetic parameters. This study yielded information for the design of further NAAA inhibitors.