Synthesis and biological evaluation of novel endocannabinoid probes, metabolically stable analogs, and N-acylethanolamine-hydrolyzing acid amidase ihibitors
Permanent URL:
http://hdl.handle.net/2047/d20002788
Jones, Graham (Committee member)
Paronis, Carol (Committee member)
Hanson, Robert (Committee member)
Our laboratory has developed ligand-assisted protein structure (LAPS) an approach which involves the combined use of covalent ligands, CB1 and CB2 mutants, as well as LC/MS based proteomic methods. We have designed a convergent synthesis for a series of potent and metabolically stable anandamide based covalent ligands. These ligands contain either an azide or isothiocyanate group in strategic sites for covalent binding to determine where this class of ligands activates the GPCR.
2-Arachidonoylglycerol (2-AG) is an important endogenous signaling molecule towards the cannabinoid receptors, however, the chemical and metabolic instability of 2-AG is a hindrance to its study. Previous chemical syntheses used conditions that promote acyl migration to the more stable 1(3)-AG. Thus, we have developed an efficient and condition neutral chemoenzymatic synthesis where minimal, if any, acyl migration is observed. Concordantly, in vivo study of 2-AG is difficult due to its short duration of action caused by hydrolysis from monoacylglycerol lipase (MAGL). Synthesis of a metabolically stable 2-AG analog has been developed to prevent MAGL metabolism.
Palmitoylethanolamine (PEA) is recognized as a naturally occurring anti-inflammatory agent that has been shown to enhance the effect of anandamide. The metabolism of PEA is controlled by N-acylethanolamine-hydrolyzing acid amidase (NAAA) and inhibition of this enzyme will increase PEA levels. Thus, we have synthesized a series of selective and reversible inhibitors of NAAA with IC50 values in the low nM range.
Anandamide
Covalent Probes
Endocannabinoid
N-Acylethanolamine-hydrolyzing acid amidase
Chemistry
Medicinal-Pharmaceutical Chemistry
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