Chiral investigation of midodrine, a long-acting α-adrenergic stimulating agent

• Published in: Chirality (New York, N.Y.) N.Y.), 2004, Vol.16 (6), p.356-362
• Main Authors: Quaglia, M.G., Farina, A., Palmery, M., Desideri, N., Donati, E., Bossù, E., Strano, S.
• Format: Article
• Language: English
• Subjects: Adrenergic alpha-Agonists - chemistry; Adrenergic alpha-Agonists - pharmacology; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - pathology; Carbon - chemistry; chiral chromatography; deglymidodrine; Dose-Response Relationship, Drug; Electrophoresis, Capillary; Hydrolysis; midodrine; Midodrine - analogs & derivatives; Midodrine - chemistry; Midodrine - pharmacology; Models, Chemical; pure enantiomer; Rabbits; racemates; Stereoisomerism
• ISSN: 0899-0042; 1520-636X
• DOI: 10.1002/chir.20041

Midodrine hydrochloride is a peripheral α1‐adrenoreceptor agonist that induces venous and arterial vasoconstriction. Midodrine, after oral or intravenous administration, undergoes enzymatic hydrolysis and releases deglymidodrine, a pharmacologically active metabolite. Midodrine and deglymidodrine have a chiral carbon in the 2‐position. To investigate the bioactivity of racemates and enantiomers of the drug and metabolite, three chromatographic chiral stationary phases, Chiralcel OD‐H, Chiralcel OD‐R, and α1‐AGP, were evaluated for enantiomeric resolution. Good enantioseparation of midodrine racemate was obtained using the Chiralcel OD‐H column. This stationary phase was then used to collect separately the midodrine enantiomers. By alkaline hydrolysis of rac‐midodrine and each separated enantiomer, rac‐deglymidodrine and its enantiomers were prepared. The control of the enantiomeric purity was carried out by α1‐AGP stationary phase, while the hydrolysis of rac‐midodrine and its enantiomers was controlled by capillary electrophoresis using trimethyl‐β‐cyclodextrin as chiral selector. The pharmacological activity of the two racemates and the two enantiomeric pairs was tested in vitro on a strip of rabbit descending thoracic aorta. The tests continued that the activity of the drug and metabolite is due only to the (−)‐enantiomer because neither of the (+)‐enantiomers is active. Chirality 16:356–362, 2004. ©2004 Wiley‐Liss, Inc.