IODINATED TOMOXETINE DERIVATIVES AS SELECTIVE LIGANDS FOR SEROTONIN AND NOREPINEPHRINE UPTAKE SITES

被引:33
作者
CHUMPRADIT, S
KUNG, MP
PANYACHOTIPUN, C
PRAPANSIRI, V
FOULON, C
BROOKS, BP
SZABO, SA
TEJANIBUTT, S
FRAZER, A
KUNG, HF
机构
[1] UNIV PENN, DEPT RADIOL, RM 305, 3700 MARKET ST, PHILADELPHIA, PA 19104 USA
[2] UNIV PENN, DEPT PSYCHIAT, PHILADELPHIA, PA 19104 USA
关键词
D O I
10.1021/jm00101a029
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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(i), 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(i) values = 0.24 and 9.35 nM for R and S isomers, respectively). The in vitro binding data suggest that 1R and 4R are potential radioiodinated ligands for pharmacological studies of 5-HT and NE uptake sites, respectively.
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页码:4492 / 4497
页数:6
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