The abuse potential of two novel synthetic cathinones with modification on the alpha-carbon position, 2-cyclohexyl-2-(methylamino)-1-phenylethanone (MACHP) and 2-(methylamino)-1-phenyloctan-1-one (MAOP), and their effects on dopaminergic activity

The recreational use of synthetic cathinones has dramatically increased in recent years, which is partly due to easy accessibility and ability of synthetic cathinones to exert rewarding effects similar to cocaine and methamphetamine. Many synthetic cathinones have already been scheduled in several countries; however, novel and diverse synthetic cathinones are emerging at an unprecedented rate, often outpacing regulatory processes. Recently, designer modifications of the basic cathinone molecule are usually performed on the alpha-carbon position. In this study, we designed and synthesized two novel synthetic cathinones with substituents on alpha-carbon position, [1] 2-cyclohexyl-2-(methylamino)-1-phenylethanone (MACHP), and [2] 2-(methylamino)-1-phenyloctan-1-one (MAOP). Then, we evaluated their rewarding and reinforcing effects through the conditioned place preference (CPP) in mice and self-administration (SA) test in rats. Locomotor activity was also assessed in mice during daily MACHP or MAOP treatment for 7 days and drug challenge. qRT-PCR analyses were conducted to determine their effects on dopamine-related genes in the striatum. MACHP and MAOP produced CPP at 10 and 30 mg/kg. In the SA test, MACHP (1 mg/kg/infusion), but not MAOP, was self-administered. Both MACHP and MAOP induced locomotor sensitization in mice. qRT-PCR analyses showed that MACHP and MAOP reduced dopamine transporter gene expression in the striatum. These data indicate that MACHP and MAOP may have rewarding properties, which might be attributed to their ability to affect the dopaminergic activity. These findings may be useful in predicting the abuse potential and hasten the regulation of future cathinone entities with similar modifications.