Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter

Mark Froimowitz, Yonghong Gu, Les A. Dakin, Pamela M. Nagafuji, Charles J. Kelley, Damon Parrish, Jeffrey R. Deschamps, Aaron Janowsky

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with different phenyl substituents, have been synthesized and tested in monoamine transporter assays.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

Original languageEnglish (US)
Pages (from-to)219-232
Number of pages14
JournalJournal of Medicinal Chemistry
Volume50
Issue number2
DOIs
StatePublished - Jan 25 2007

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Dopamine Plasma Membrane Transport Proteins
Methylphenidate
Assays
Carbon
Dopamine Uptake Inhibitors
Ketones
Cocaine
Amides
Atoms

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. / Froimowitz, Mark; Gu, Yonghong; Dakin, Les A.; Nagafuji, Pamela M.; Kelley, Charles J.; Parrish, Damon; Deschamps, Jeffrey R.; Janowsky, Aaron.

In: Journal of Medicinal Chemistry, Vol. 50, No. 2, 25.01.2007, p. 219-232.

Research output: Contribution to journalArticle

Froimowitz, Mark ; Gu, Yonghong ; Dakin, Les A. ; Nagafuji, Pamela M. ; Kelley, Charles J. ; Parrish, Damon ; Deschamps, Jeffrey R. ; Janowsky, Aaron. / Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. In: Journal of Medicinal Chemistry. 2007 ; Vol. 50, No. 2. pp. 219-232.
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AU - Nagafuji, Pamela M.

AU - Kelley, Charles J.

AU - Parrish, Damon

AU - Deschamps, Jeffrey R.

AU - Janowsky, Aaron

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