We recently discovered and reported a novel series of benzhydrylpiperazine derivatives bearing an asymmetric carbon atom that are potent and selective hCB1 inverse agonists. In the present study, we used Davis-Ellmann-type sulfonamide chemistry to asymmetrically synthesize two enantiomers of the most potent racemic N-cyclohexyl-4-[1-(2,4-dichlorophenyl)-1-(p-tolyl)methyl]piperazine-1-carbo-xamide [14]. Enantiomer separation and configuration assignment were carried out. Our results indicate that the R-configuration is the more active enantiomer, displaying enhanced antagonistic activity for hCB1 receptor, better oral bioavailability, and greater efficacy in the reduction of body weight in diet-induced obese mice.Description: Asymmetric synthesis of benzhydrylpiperazines 13S and 13R revealed that 13R is the more active enantiomer, displaying enhanced antagonistic activity for hCB1R, better oral bioavailability, and greater efficacy in the reduction of body weight in diet-induced obese mice.Highlights► We synthesized the enantiomers of hCB1 inverse agonist 13R and 13S. ► Results indicated that the (R)-enantiomer is more active. ► In vivo study showed enhanced antagonistic activity for hCB1, and better bio-efficacy.