Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling.

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Lapinsky DJ, Velagaleti R, Yarravarapu N, Liu Y, Huang Y, Surratt CK, Lever JR, Foster JD, Acharya R, Vaughan RA, Deutsch HM

Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling.

Bioorg Med Chem. 2011 Jan 1;19(1):504-12. doi: 10.1016/j.bmc.2010.11.002. Epub 2010 Nov 4.

PubMed ID

21129986 [ View in PubMed

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Abstract

In contrast to tropane-based compounds such as benztropine and cocaine, non-tropane-based photoaffinity ligands for the dopamine transporter (DAT) are relatively unexplored. Towards addressing this knowledge gap, ligands were synthesized in which the piperidine nitrogen of 3- and 4-iodomethylphenidate was substituted with a benzyl group bearing a photoreactive azide. Analog (+/-)-3a demonstrated modest DAT affinity and a radioiodinated version was shown to bind covalently to rat striatal DAT and hDAT expressed in cultured cells. Co-incubation of (+/-)-3a with nonradioactive d-(+)-methylphenidate or (-)-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane (beta-CFT, WIN-35,428, a cocaine analog) blocked DAT labeling. Compound (+/-)-3a represents the first successful example of a DAT photoaffinity ligand based on the methylphenidate scaffold. Such ligands are expected to assist in mapping non-tropane ligand-binding pockets within plasma membrane monoamine transporters.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Dexmethylphenidate	Sodium-dependent dopamine transporter	IC 50 (nM)	156	N/A	N/A	Details
Dexmethylphenidate	Sodium-dependent dopamine transporter	Ki (nM)	25	N/A	N/A	Details