Synthesis and biological evaluation of 2-substituted 3β-tolyltropane derivatives at dopamine, serotonin, and norepinephrine transporters

Lifen Xu, Sari E Izenwasser, Jonathan L. Katz, Theresa Kopajtic, Cheryl Klein-Stevens, Naiju Zhu, Stacey A. Lomenzo, Leyte Winfield, Mark L. Trudell

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Abstract

A series of eight 2-substituted 3-tolyltropane derivatives were synthesized, and the in vitro and in vivo biological activities as dopamine uptake inhibitors were determined. From the in vitro structure-activity data, it is apparent that a tolyl group in the 2-position, independent of the stereochemical attachment to the tropane ring system, provided compounds (9-12, 14) that exhibit high-affinity binding at the dopamine transporter (DAT). Although a slight stereochemical preference in binding affinity at the DAT was observed for the 2β-(R)-alcohol 10 over the 2β-(S)-isomer 11, no significant differences in behavioral effects were observed. Furthermore, despite a relatively low potency of 10 for the inhibition of dopamine uptake compared to its affinity for the DAT, its behavioral profile did not vary significantly from cocaine. These data indicate that a behavioral characterization of compounds is a critical feature of efforts to discover pharmacological treatments for cocaine abuse.

Original languageEnglish
Pages (from-to)1203-1210
Number of pages8
JournalJournal of Medicinal Chemistry
Volume45
Issue number6
DOIs
StatePublished - Mar 14 2002

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Norepinephrine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Derivatives
Cocaine
Dopamine Uptake Inhibitors
Tropanes
Cocaine-Related Disorders
Bioactivity
Isomers
Dopamine
Alcohols
Pharmacology
In Vitro Techniques

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis and biological evaluation of 2-substituted 3β-tolyltropane derivatives at dopamine, serotonin, and norepinephrine transporters. / Xu, Lifen; Izenwasser, Sari E; Katz, Jonathan L.; Kopajtic, Theresa; Klein-Stevens, Cheryl; Zhu, Naiju; Lomenzo, Stacey A.; Winfield, Leyte; Trudell, Mark L.

In: Journal of Medicinal Chemistry, Vol. 45, No. 6, 14.03.2002, p. 1203-1210.

Research output: Contribution to journalArticle

Xu, Lifen ; Izenwasser, Sari E ; Katz, Jonathan L. ; Kopajtic, Theresa ; Klein-Stevens, Cheryl ; Zhu, Naiju ; Lomenzo, Stacey A. ; Winfield, Leyte ; Trudell, Mark L. / Synthesis and biological evaluation of 2-substituted 3β-tolyltropane derivatives at dopamine, serotonin, and norepinephrine transporters. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 6. pp. 1203-1210.
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AU - Kopajtic, Theresa

AU - Klein-Stevens, Cheryl

AU - Zhu, Naiju

AU - Lomenzo, Stacey A.

AU - Winfield, Leyte

AU - Trudell, Mark L.

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