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NEUROPHARMACOLOGY
Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (R.B.R., N.V., J.S.P.); Departments of Biochemistry, Neuroscience, and Psychiatry and the National Institutes of Mental Health Psychoactive Drug Screening Program, Case Western Reserve University School of Medicine, Cleveland, Ohio (B.L.R., S.J.H., B.A.C.-T., J.B.); and Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (R.Y., R.A.G.)
Ephedrine is a long-studied stimulant available both as a prescription and over-the-counter medication, as well as an ingredient in widely marketed herbal preparations, and is also used as a precursor for the illicit synthesis of methamphetamine. Ephedrine is related to phenylpropanolamine, a decongestant removed from the market place due to concerns that its use increased the risk of hemorrhagic stroke. Standard pharmacology texts emphasize that ephedrine is both a direct and indirect adrenergic agonist, activating adrenergic receptors both by direct agonist activity as well as by releasing norepinephrine via a carrier-mediated exchange mechanism. Chemically, ephedrine possesses two chiral centers. In the present study, we characterized the stereoisomers of ephedrine and the closely related compounds pseudoephedrine, norephedrine, pseudonorephedrine (cathine), methcathinone, and cathinone at biogenic amine transporters and a large battery of cloned human receptors (e.g., "receptorome"). The most potent actions of ephedrine-type compounds were as substrates of the norepinephrine transporter (EC50 values of about 50 nM) followed by substrate activity at the dopamine transporter. Screening the receptorome demonstrated weak affinity at 
2-adrenergic and 5-hydroxytryptamine7 receptors (Ki values 1–10 µM) and no significant activity at 
-adrenergic or 1-adrenergic receptors. Viewed collectively, these data indicate that the pharmacological effects of ephedrine-like phenylpropanolamines are likely mediated by norepinephrine release, and although sharing mechanistic similarities with, they differ in important respects from those of the phenylpropanonamines methcathinone and cathinone and the phenyisopropylamines methamphetamine and amphetamine.
Address correspondence to: Dr. Richard B. Rothman, Clinical Psychopharmacology Section, Division of Intramural Research, National Institute on Drug Abuse, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224. E-mail: rrothman{at}intra.nida.nih.gov
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