Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter.
Article Details
- CitationCopy to clipboard
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]
- 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Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with different phenyl substituents, have been synthesized and tested in monoamine transporter assays.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