Effects of N-alkyl-4-methylamphetamine optical isomers on plasma membrane monoamine transporters and abuse-related behavior.

4-Methylamphetamine (4-MA) is an emerging drug of abuse that acts as a substrate at plasma membrane transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT), thereby causing non-exocytotic release of monoamine transmitters via reverse transport. Prior studies show that increasing the N-alkyl chain length of 4-MA converts the agent from a transportable substrate (i.e., releaser) at DAT and NET to a non-transported blocker at these sites. Here we studied the effects of stereoisomers of N-methyl-, N-ethyl-, and N-n-propyl 4-MA on monoamine transporters and abuse-related behavior in rats. Uptake inhibition and release assays were carried out in rat brain synaptosomes whereas electrophysiological assessments of drug-transporter interactions were examined using cell-based biosensors. Intracranial-self stimulation in rats was employed to assess abuse potential in vivo. The experimental evidence demonstrates that S(+)N-methyl 4-MA is a potent and efficacious releaser at DAT, NET, and SERT with the highest abuse potential among the test drugs whereas R(-)N-methyl 4-MA, is a less potent releaser with reduced abuse potential. The S(+)ethyl analog displays decreased efficacy as a releaser at DAT but retains full release activity at NET and SERT with a reduction in abuse-related effects; the R(-)ethyl analog has a similar profile but is less potent. S(+)N-Propyl 4-MA is a non-transported blocker at DAT and NET, but an efficacious releaser at SERT, whereas the R enantiomer is almost inactive. In conclusion, the S enantiomers of the N-alkyl 4-MA analogs are most potent. Lengthening the N-alkyl chain converts compounds from a potent non-selective releaser showing abuse-related effects, to more selective SERT releasers with no abuse potential.