Sn-1 diacylglycerol lipase-α (DAGL-α) is the main enzyme responsible for the production of the endocannabinoid 2-arachidonoylglycerol in the central nervous system. Glycine sulfonamides have recently been identified by a high throughput screenings campaign as a novel class of inhibitors for this enzyme. Here, we report on the first structure-activity relationship study of glycine sulfonamide inhibitors and their brain membrane proteome-wide selectivity on serine hydrolases with activity-based protein profiling (ABPP). We found that i) DAGL-α tolerates a variety of biaryl substituents, ii) the sulfonamide is required for inducing a specific orientation of the 2,2-dimethylchroman substituent and iii) a carboxylic acid is essential for its activity. ABPP revealed that the sulfonamide glycine inhibitors have at least three off-targets, including α-β-hydrolase domain 6 (ABHD6). Finally, we identified LEI-106 as a potent, dual DAGL-α/ABHD6 inhibitor, which makes this compound a potential lead for the discovery of new molecular therapies for diet-induced obesity and metabolic syndrome.