In Vitro Characterization of Ephedrine-Related Stereoisomers at Biogenic Amine Transporters and the Receptorome Reveals Selective Actions as Norepinephrine Transporter Substrates

• Published in: The Journal of pharmacology and experimental therapeutics 2003-10, Vol.307 (1), p.138-145
• Main Authors: Rothman, Richard B, Vu, Nga, Partilla, John S, Roth, Bryan L, Hufeisen, Sandra J, Compton-Toth, Beth A, Birkes, Jon, Young, Richard, Glennon, Richard A
• Format: Article
• Language: English
• Subjects: Adrenergic Agents - pharmacology; Alkaloids - chemistry; Alkaloids - pharmacology; Animals; Biogenic Amines - metabolism; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins; Ephedrine - chemistry; Ephedrine - pharmacology; Humans; Male; Membrane Glycoproteins; Membrane Transport Proteins - drug effects; Membrane Transport Proteins - metabolism; Nerve Tissue Proteins; Norepinephrine - metabolism; Norepinephrine Plasma Membrane Transport Proteins; Rats; Rats, Sprague-Dawley; Serotonin - metabolism; Stereoisomerism; Structure-Activity Relationship; Symporters - drug effects; Symporters - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.053975

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 (EC 50 values of about 50 nM) followed by substrate activity at the dopamine transporter. Screening the receptorome demonstrated weak affinity at α 2 -adrenergic and 5-hydroxytryptamine 7 receptors ( K i values 1–10 μM) and no significant activity at β-adrenergic or α 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.