Slow-Onset, Long-Duration, Alkyl Analogues of Methylphenidate with Enhanced Selectivity for the Dopamine Transporter

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• 作者：Mark Froimowitz ; Yonghong Gu ; Les A. Dakin ; Pamela M. Nagafuji ; Charles J. Kelley ; Damon Parrish ; Jeffrey R. Deschamps ; Aaron Janowsky
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：January 25, 2007
• 年：2007
• 卷：50
• 期：2
• 页码：219 - 232
• 全文大小：204K
• 年卷期：v.50,no.2(January 25, 2007)
• ISSN：1520-4804

文摘

Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with differentphenyl substituents, have been synthesized and tested in monoamine transporter assays. As predicted froma pharmacophore model, most of the RR/SS diastereomers showed high potency as dopamine reuptakeinhibitors. Analogues with a 4-chlorophenyl group and an unbranched initial alkyl atom had consistentlyenhanced selectivity for the dopamine transporter. The most potent compounds were those with a three- orfour-carbon chain. The "inactive" RS/SR diastereomers showed substantial activity when the phenyl substituentwas 3,4-dichloro. On a locomotor assay, one compound was found to have a slow onset and a long durationof action. The activity of these compounds provides additional evidence for a conformational/superpositionmodel of methylphenidate with cocaine-like structures. A ketone analogue, obtained by hydrogenating apreviously described vinylogous amide, had activity similar to that of methylphenidate.