Stereospecific inhibition of monoamine uptake transporters by meta-hydroxyephedrine isomers

• Published in: Journal of Neural Transmission Vol. 109; no. 10; pp. 1229 - 1240
• Main Authors: FOLEY, K. F, VAN DORT, M. E, SIEVERT, M. K, RUOHO, A. E, COZZI, N. V
• Format: Journal Article
• Language: English
• Published: Wien Springer 01-10-2002; New York, NY Springer Nature B.V
• Subjects: Animals; Biogenic Monoamines - metabolism; Biological and medical sciences; Blood Platelets - drug effects; Blood Platelets - metabolism; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - chemistry; Cattle; Cell Membrane - metabolism; Cells, Cultured; Chromaffin Granules - drug effects; Chromaffin Granules - metabolism; Dopamine - metabolism; Ephedrine - analogs & derivatives; Ephedrine - pharmacology; Malformations of the eye; Medical sciences; Membrane Glycoproteins - metabolism; Membrane Transport Proteins; Neuropeptides; Norepinephrine - metabolism; Ophthalmology; Serotonin - metabolism; Stereoisomerism; Transfection; Vesicular Biogenic Amine Transport Proteins; Stereoisomer; Dopamine; Structure activity relation; Neurotransmitter; Stereospecificity; Inhibition; Catecholamine; Substrate analog; Carrier protein
• ISSN: 0300-9564; 1435-1463
• DOI: 10.1007/s00702-002-0695-6

Meta-hydroxyephedrine (HED) comprises four stereoisomers consisting of two enantiomeric pairs related to ephedrine and pseudoephedrine. HED is transported into adrenergic neurons and radiolabeled HED has been employed in positron emission tomography (PET) to image adrenergic neurons in vivo. To extend structure-activity analyses of binding sites within monoamine transporters and to determine which stereoisomer displayed the best selectivity for PET imaging applications, we tested the HED compounds for their abilities to inhibit [(3)H]neurotransmitter uptake into platelets, transfected cells, and chromaffin vesicles. We hypothesized that the HED compounds would be most potent at the norepinephrine transporter (NET) compared to the serotonin or dopamine transporters and that the 1R diastereomers would be more effective than 1S diastereomers. Supporting the hypotheses, all stereoisomers were most potent at the NET and the 1R,2S stereoisomer was the most potent inhibitor overall. However, the 1S,2R isomer may be preferred for PET applications because of better selectivity among the transporters and reduced neuronal recycling.