Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta)

Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)504-512
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

Fingerprint

Dopamine Plasma Membrane Transport Proteins
Methylphenidate
Labeling
Pharmacology
Ligands
Derivatives
Cocaine
Bearings (structural)
Benztropine
Tropanes
Corpus Striatum
Membrane Transport Proteins
Azides
Cell membranes
Scaffolds
Rats
Cultured Cells
Nitrogen
Cells
Cell Membrane

Keywords

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

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

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

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 1, 01.01.2011, p. 504-512.

Research output: Contribution to journalArticle

Lapinsky, DJ, Velagaleti, R, Yarravarapu, N, Liu, Y, Huang, Y, Surratt, CK, Lever, JR, Foster, JD, Acharya, R, Vaughan, RA & Deutsch, HM 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, vol. 19, no. 1, pp. 504-512. https://doi.org/10.1016/j.bmc.2010.11.002
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. / Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta) : Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 1. pp. 504-512.
@article{5c8e2786b4004fe5b86844cf06a280cb,
title = "Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling",
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.",
keywords = "Attention-deficit hyperactivity disorder, Cocaine, Concerta, Dopamine transporter, Methylphenidate, Photoaffinity labeling, Ritalin",
author = "Lapinsky, {David J.} and Ranganadh Velagaleti and Nageswari Yarravarapu and Yi Liu and Yurong Huang and Surratt, {Christopher K.} and Lever, {John R.} and Foster, {James D.} and Rejwi Acharya and Vaughan, {Roxanne A.} and Deutsch, {Howard M.}",
year = "2011",
month = "1",
day = "1",
doi = "10.1016/j.bmc.2010.11.002",
language = "English (US)",
volume = "19",
pages = "504--512",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "1",

}

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.

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 - http://www.scopus.com/inward/record.url?scp=78650753273&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650753273&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2010.11.002

DO - 10.1016/j.bmc.2010.11.002

M3 - Article

VL - 19

SP - 504

EP - 512

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 1

ER -