Synthesis, pharmacological activity and chromatographic separation of some novel potential beta-blockers of the aryloxyaminopropanol type.
Following our previous structure-activity relationship studies, some novel compounds of the aryloxyaminopropanol type, derived from 2- or 4-hydroxyphenylalkanones, with phenethyl or 3,4-dimethoxyphenethyl groups in the hydrophilic part of the molecule were synthesized and pharmacologically evaluated. The compounds were prepared by means of two methods and their structures were confirmed by the interpretation of their IR, UV and 1H NMR spectra. The enantiomers were separated by HPLC on vancomycin (Chirobiotic V) and teicoplanin (Chirobiotic T) chiral stationary phases. The affinity of the prepared racemic compounds to beta1- and beta2-adrenergic receptors was pre-determined on isolated guinea pig atria and trachea. The assumed cardioselectivity was expressed as the beta1/beta2 ratio. Reciprocal changes in the position of the phenoxysubstituents did not influence the antiisoprenaline activity of the compounds. On the other hand, the increase of the N-substituent size in the hydrophilic part of molecule (3,4-dimethoxyphenethyl moietyled to a substantially higher affinity for cardiac (beta1) than for tracheal (beta2) tissue.
Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia. cizmarikova@fpharm.uniba.sk
R
R
Cizmáriková
E
E
Racanská
K
K
Hrobonova
J
J
Lehotay
Z
Z
Aghová
D
D
Halesová
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology*; D000465:Algorithms; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D020005:Propanols / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D014132:Trachea / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D020005:Propanols; D007545:Isoproterenol