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

David J. Lapinsky, Ranganadh Velagaleti, Nageswari Yarravarapu, Yi Liu, Yurong Huang, Christopher K. Surratt, John R. Lever, James D. Foster, Rejwi Acharya, Roxanne A. Vaughan, Howard M. Deutsch

Research output: Contribution to journalArticle

11 Scopus citations

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-β-carbomethoxy-3-β-(4-fluorophenyl)tropane (β-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.

Original languageEnglish (US)
Pages (from-to)504-512
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2011

Keywords

  • Attention-deficit hyperactivity disorder
  • Cocaine
  • Concerta
  • Dopamine transporter
  • Methylphenidate
  • Photoaffinity labeling
  • Ritalin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Lapinsky, D. J., Velagaleti, R., Yarravarapu, N., Liu, Y., Huang, Y., Surratt, C. K., Lever, J. R., Foster, J. D., Acharya, R., Vaughan, R. A., & Deutsch, H. M. (2011). Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling. Bioorganic and Medicinal Chemistry, 19(1), 504-512. https://doi.org/10.1016/j.bmc.2010.11.002