Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling
Bioorganic and Medicinal Chemistry
Attention-deficit hyperactivity disorder, Cocaine, Concerta, Dopamine transporter, Methylphenidate, Photoaffinity labeling, Ritalin
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.
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