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

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Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, Deschamps JR, Janowsky A

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

J Med Chem. 2007 Jan 25;50(2):219-32.

PubMed ID

17228864 [ View in PubMed

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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Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with different phenyl substituents, have been synthesized and tested in monoamine transporter assays.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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Methylphenidate	Sodium-dependent dopamine transporter	Ki (nM)	110	N/A	N/A	Details
Methylphenidate	Sodium-dependent dopamine transporter	IC 50 (nM)	79	N/A	N/A	Details
Methylphenidate	Sodium-dependent noradrenaline transporter	Ki (nM)	660	N/A	N/A	Details
Methylphenidate	Sodium-dependent noradrenaline transporter	IC 50 (nM)	61	N/A	N/A	Details