Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling.
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.
Division of Pharmaceutical Sciences, Duquesne University Mylan School of Pharmacy, 600 Forbes Avenue, Pittsburgh, PA 15282, USA. lapinskyd@duq.edu
David J
DJ
Lapinsky
Ranganadh
R
Velagaleti
Nageswari
N
Yarravarapu
Yi
Y
Liu
Yurong
Y
Huang
Christopher K
CK
Surratt
John R
JR
Lever
James D
JD
Foster
Rejwi
R
Acharya
Roxanne A
RA
Vaughan
Howard M
HM
Deutsch
D002851:Chromatography, High Pressure Liquid; D050483:Dopamine Plasma Membrane Transport Proteins / Q000737:chemistry*; D015195:Drug Design; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008774:Methylphenidate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D019920:Photoaffinity Labels; D013329:Structure-Activity Relationship
D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D019920:Photoaffinity Labels; D008774:Methylphenidate