Iodinated Tomoxetine Derivatives as Selective Ligands for Serotonin and Norepinephrine Uptake Sites

Mei Ping Rung, Shanaz Tejani-butt, Alan Frazer, Brian P. Brooks, Stephen A. Szabo, Hank F. Hung, Sumalee Chumpradit, Chitchanum Panyachotipun, Vichukorn Prapanairi, Catherine Foulon

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

In order to develop selective radioactive ligands for the study of presynaptic monoamine uptake sites, iodinated derivatives of tomoxetine were synthesized and evaluated in radioligand binding assays. Iodotomoxetine derivatives showed high affinity for serotonin (5-HT) uptake sites using a rat cortical membrane preparation. Compound 1R, (R)-(-)-N-methyl-3-(4-iodo-2-methylphenoxy)-3-phenylpropanamine, was the most potent and showed high stereoselectivity for 5-HT uptake sites (K¡, R isomer = 0.65 nM, S isomer = 13.9 nM). Changing the position of the methyl group or eliminating the methyl group at the phenoxy ring resulted in a loss of stereoselectivity. Substitution of the methyl group of tomoxetine with iodine gave the R and S isomers of N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine 4R and 4S. These compounds displayed stereoselectivity for the norepinephrine (NE) (K¡ values = 0.24 and 9.35 nM for R and S isomers, respectively). The in vitro binding data suggest that IR and 4R are potential radioiodinated ligands for pharmacological studies of 5-HT and NE uptake sites, respectively.

Original languageEnglish (US)
Pages (from-to)4492-4497
Number of pages6
JournalJournal of Medicinal Chemistry
Volume35
Issue number23
DOIs
StatePublished - Nov 1 1992
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Rung, M. P., Tejani-butt, S., Frazer, A., Brooks, B. P., Szabo, S. A., Hung, H. F., Chumpradit, S., Panyachotipun, C., Prapanairi, V., & Foulon, C. (1992). Iodinated Tomoxetine Derivatives as Selective Ligands for Serotonin and Norepinephrine Uptake Sites. Journal of Medicinal Chemistry, 35(23), 4492-4497. https://doi.org/10.1021/jm00101a029