Chiral Resolution of the Enantiomers of the Slow-Onset Dopamine Reuptake Inhibitor CTDP-32476 and Their Activities.

Abstract

An improved synthesis was developed for CDTP-32476, a potent slow-onset dopamine reuptake blocker that may have utility as a treatment for cocaine abuse. The enantiomers of the compound were separated by fractional crystallization with N-acetylleucine enantiomers. An X-ray crystal structure was obtained of the RR enantiomer paired with N-acetyl-d-leucine. Chiral chromatography showed that the resolved enantiomers were pure with little contamination by the other enantiomer. The enantiomers were tested for their ability to block the reuptake of monoamines at their respective transporters and to stimulate locomotor activity in mice. Both enantiomers potently blocked the reuptake of dopamine and stimulated locomotor activity in mice. The RR enantiomer that corresponds to the active RR enantiomer of methylphenidate was slightly more potent at the dopamine reuptake site. The RR enantiomer also was found to be about twice as selective for the dopamine transporter relative to the norepinephrine transporter, which may have clinical implications. A method for designing slow-onset stimulants is proposed since there is increasing evidence that such activity is an important factor in stimulants that may have limited abuse potential.