Synthesis and evaluation of dopamine and serotonin transporter inhibition by oxacyclic and carbacyclic analogues of methylphenidate.

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Meltzer PC, Wang P, Blundell P, Madras BK

Synthesis and evaluation of dopamine and serotonin transporter inhibition by oxacyclic and carbacyclic analogues of methylphenidate.

J Med Chem. 2003 Apr 10;46(8):1538-45.

PubMed ID
12672255 [ View in PubMed
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Abstract

Methylphenidate (Ritalin) binds stereoselectively and enantioselectively to the dopamine transporter (DAT) and inhibits dopamine reuptake with in vitro and in vivo potency similar to that of cocaine. Unlike cocaine, it manifests little, if any, tolerance or addiction liability. Since this compound has a substantial clinical history, it provides an excellent template from which to design potential medications for cocaine abuse. It has long been assumed that a nitrogen, such as exists in cocaine and methylphenidate, is essential for interaction with monoamine transporters. We previously demonstrated that an amine nitrogen in phenyltropane analogues of cocaine is not necessary for conferring high DAT binding affinity. We now report the synthesis of oxacyclic and carbacyclic analogues of methylphenidate, including the four enantiomerically pure isomers of 2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yl)acetic acid methyl ester. The threo isomers are potent and selective inhibitors of the DAT. This is the first generalization of the principle that the presence of nitrogen is not a necessity for DAT inhibition.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
DexmethylphenidateSodium-dependent dopamine transporterIC 50 (nM)88N/AN/ADetails
MethylphenidateSodium-dependent dopamine transporterIC 50 (nM)1200N/AN/ADetails
MethylphenidateSodium-dependent dopamine transporterIC 50 (nM)17N/AN/ADetails