Society for Neuroscience Abstracts, 26, 819.20 (2000)

Stereochemical effects of meta-hydroxyephedrine isomers at monoamine uptake transporters: a structure-activity study.

Kevin F. Foley, Marcian E. Van Dort,* and Nicholas V. Cozzi

Department of Pharmacology, Brody School of Medicine, East Carolina University, Greenville, NC 27834

*Division of Nuclear Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109

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Abstract

Meta-hydroxyephedrine (HED) is a catecholamine analog that is accumulated within adrenergic neurons. A radiolabeled form of the drug, 1R,2S [¹¹C]HED, has been employed as a positron emission tomography tracer to image adrenergic neurons in vivo. HED comprises four stereoisomers that consist of two enantiomeric pairs related to ephedrine (erythro configuration) or pseudoephedrine (threo configuration). To extend our structure-activity analysis of drug binding sites within the monoamine neurotransmitter uptake carriers, we synthesized and tested the four stereoisomers of HED for their abilities to inhibit monoamine neurotransmitter uptake in vitro. A mixture containing the four normethyl precursors of HED was synthesized from propiophenone. The individual normethyl stereoisomers were then isolated and converted to the corresponding HED stereoisomers. At the cloned human norepinephrine transporter (NET), the 1R,2S HED stereoisomer was the most potent inhibitor of [³H]norepinephrine uptake with an IC₅₀ of 422 ± 40 nM, while the 1R,2R isomer was 16-fold less potent, with an IC₅₀ of 6.95 ± ±1.06 uM; the 1S,2R and 1S,2S isomers were intermediate in potency with IC₅₀ values of about 1 uM. All of the HED stereoisomers were weak inhibitors of [³H]serotonin uptake into human platelets, with IC₅₀ values in excess of 30 uM.

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