Investigation of the Optical Isomers of Methcathinone, and Two Achiral Analogs, at Monoamine Transporters and in Intracranial Self-Stimulation Studies in Rats

Abstract

Methcathinone (MCAT; 1), the progenitor of numerous and widely abused “synthetic cathinone” central stimulants, exists as a pair of optical isomers. Although S(−)­MCAT is several-fold more potent than R(+)­MCAT in rodent locomotor stimulation and in stimulus generalization studies in rat drug discrimination assays, the individual optical isomers of MCAT have never been directly compared for their actions at monoamine transporters that seem to underlie their actions and have never been examined for their relative abuse potential. Here, we found that the isomers of MCAT are nearly equieffective at dopamine and norepinephrine transporters (DAT and NET, respectively) as transporter substrates (i.e., as releasing agents) and are ≥63-fold less potent at the serotonin transporter (SERT). In intracranial self-stimulation (ICSS) studies to evaluate abuse-related drug effects in rats, S(−)­MCAT was approximately twice as potent as its R-enantiomer. Achiral analogs, α-methyl MCAT (3) and α-des-methyl MCAT (4), also were DAT/NET substrates and also produced abuse-related ICSS effects, indicating that they retain abuse potential and that they might be useful for the further study of the stereochemistry of synthetic cathinone analogs with chiral β- (or other) substituents.

Synthetic Cathinones: Recent Developments, Enantioselectivity Studies and Enantioseparation Methods

“…Davies et al [ 70 ] studied the actions of the enantiomers of methcathinone ( 8 ) at monoamine transporters, discovering that they presented similar inhibition potencies at DAT and NET. At SERT, the S -enantiomer displayed a lower potency than at DAT and NET, while the R -enantiomer was practically inactive.…”

“…At SERT, the S -enantiomer displayed a lower potency than at DAT and NET, while the R -enantiomer was practically inactive. Furthermore, in this study, an ICSS procedure to evaluate abuse-related drug effects in rats showed that the S -enantiomer presented almost twice the potency of the R -enantiomer [ 70 ].…”

Dehydrogenative Coupling of Alkylamines with Primary Alcohols Forming α-Amino Ketones

“…α-Amino ketone is a motif frequently found in bioactive molecules and natural products. − Also, it serves as a versatile synthetic intermediate for producing amino alcohols − and nitrogen-containing heterocycles. − Consequently, the development of efficient methods for constructing α-amino ketones − holds multiple implications for organic synthesis. Among various synthetic strategies for α-amino ketones, intermolecular C–C bond formation between the nitrogen-containing substrates and oxygen-containing counterparts is of particular value because it allows efficient construction of diverse carbon skeletons using readily available starting materials.…”