TY - JOUR
T1 - Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta)
T2 - Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling
AU - Lapinsky, David J.
AU - Velagaleti, Ranganadh
AU - Yarravarapu, Nageswari
AU - Liu, Yi
AU - Huang, Yurong
AU - Surratt, Christopher K.
AU - Lever, John R.
AU - Foster, James D.
AU - Acharya, Rejwi
AU - Vaughan, Roxanne A.
AU - Deutsch, Howard M.
N1 - Funding Information:
This work was funded by a Hunkele Dreaded Disease Award (D.J.L.), the Mylan School of Pharmacy at Duquesne University (D.J.L.), and NIH Grants DA27081 (D.J.L.), DA16604 (C.K.S.), and DA15175 (R.A.V.). We thank NIDA Drug Supply for contribution of certain nonradioactive DAT ligand compounds.
PY - 2011/1/1
Y1 - 2011/1/1
N2 - 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.
AB - 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.
KW - Attention-deficit hyperactivity disorder
KW - Cocaine
KW - Concerta
KW - Dopamine transporter
KW - Methylphenidate
KW - Photoaffinity labeling
KW - Ritalin
UR - https://www.scopus.com/pages/publications/78650753273
UR - https://www.scopus.com/pages/publications/78650753273#tab=citedBy
U2 - 10.1016/j.bmc.2010.11.002
DO - 10.1016/j.bmc.2010.11.002
M3 - Article
C2 - 21129986
AN - SCOPUS:78650753273
SN - 0968-0896
VL - 19
SP - 504
EP - 512
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 1
ER -