Publication Date

Spring 5-2023

School

School of Health Sciences

Major

Biology: Biomedical Sciences

Keywords

Endocannabinoid System, FAAH, MAGL, AEA, 2-AG, Dual Enzyme Inhibitor

Disciplines

Chemicals and Drugs | Enzymes and Coenzymes | Medical Biochemistry | Medicinal-Pharmaceutical Chemistry | Optometry | Organic Chemicals | Organic Chemistry

Abstract

Peripherally selective compounds have been found to stimulate endocannabinoid receptor activity, which has been observed to have positive physiological effects such as ocular wound healing and inflammation control. The activation of the cannabinoid 1 receptor via binding of the endogenous ligands, anandamide and 2-arachidonoylglycerol, has been indicated to elicit these effects. Both ligands are controlled by two hydrolase enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which can be targeted for therapeutic inhibition. Sulfonamide derivatives of JZL195 containing carbamate functionalities in the southern region of the inhibitor compounds were produced using novel carbamate exchange reactions. Polar functionalities were introduced to increase their high topological surface area (TPSA) to prevent the crossing of these inhibitors through the blood-brain barrier (BBB), which in turn prevents any potential adverse effects on the central nervous system. The potency of each compound was measured using inhibitor screening assay kits for FAAH and MAGL.

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