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

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

来源：Bioorganic & Medicinal Chemistry, 2011, 19(1): 504-512.

DOI：10.1016/j.bmc.2010.11.002

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

In contrast to tropane-based compounds such as benztropine and cocaine, non-tropane-based photo-affinity 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.

• 出版日期2011-1-1