Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling
DOI
10.1016/j.bmc.2010.11.002
Document Type
Journal Article
Publication Date
1-1-2011
Publication Title
Bioorganic and Medicinal Chemistry
Volume
19
Issue
1
First Page
504
Last Page
512
ISSN
9680896
Keywords
Attention-deficit hyperactivity disorder, Cocaine, Concerta, Dopamine transporter, Methylphenidate, Photoaffinity labeling, Ritalin
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. © 2010 Elsevier Ltd. All rights reserved.
Open Access
Green Accepted
Preprint
Repository Citation
Lapinsky, D., Velagaleti, R., Yarravarapu, N., Liu, Y., Huang, Y., Surratt, C., Lever, J., Foster, J., Acharya, R., Vaughan, R., & Deutsch, H. (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