ABHD6 signature templates: We report tetrahydroisoquinoline and isoindoline “signature templates” for ABHD6 with single-digit nanomolar inhibitory and specificity for the target, and >1000-fold selectivity against serine hydrolase MGL and FAAH. One ABHD6 inhibitor attenuated AMPA-induced glia activation and produced retinal neuroprotection in rats. These new ABHD6 inhibitors provide early leads to develop therapeutics for neuroprotection and the treatment of inflammation and diabetes.

Abstract

Fine-tuning than complete disruption of 2-arachidonoylglycerol (2-AG) metabolism in the brain represents a promising pharmacological approach to limit potential untoward effects associated with complete blockade of monoacylglycerol lipase (MGL), the primary hydrolase of 2-AG. This could be achieved through a/b-hydrolase domain containing 6 (ABHD6) inhibition, which will provide a smaller and safer contribution to 2-AG regulation in the brain. Pharmacological studies with ABHD6 inhibitors have recently been reported, where modulation of ABHD6 activity either through CB1R-dependent or CB1R-independent processes showed promise in preclinical models of epilepsy, neuropathic pain and inflammation. Furthermore in the periphery, ABHD6 modulates 2-AG and other fatty acid monoacylglycerols (MAGs) and is implicated in Type-2 diabetes, metabolic syndrome and potentially other diseases. Herein, we report the discovery of single-digit nanomolar potent and highly specific ABHD6 inhibitors with >1000-fold selectivity against MGL and FAAH. The new ABHD6 inhibitors provide early leads to develop therapeutics for neuroprotection and the treatment of inflammation and diabetes.