Cardiovascular hybrid drugs: new benzazepinone derivatives as bradycardic agents endowed with selective beta1-non-competitive antagonism.
The synthesis and pharmacological profile of some hybrid compounds bearing both the benzazepinone moiety present in Zatebradine and typical beta-blocker aryloxypropanolamine groups are described. The new compounds proved to be endowed with negative chronotropic and inotropic activity and are weak vasorelaxant agents. The cardiodepressant action is probably due to selective beta(1)-noncompetitive reversible antagonism. Both enantiomers of the most active compound 5c were synthesized and they showed a different cardiovascular profile, that is (+)-(R)-enantiomer displays affinity for cardiac beta(1)-adrenoceptors, while (-)-(S)-enantiomer shows specificity for vessel smooth muscle.
Bisi
Alessandra
A
Department of Pharmaceutical Sciences, University of Bologna, via Belmeloro 6, 40126, Bologna, Italy. albisi@alma.unibo.it
Rampa
Angela
A
Budriesi
Roberta
R
Gobbi
Silvia
S
Belluti
Federica
F
Ioan
Pierfranco
P
Valoti
Ermanno
E
Chiarini
Alberto
A
Valenti
Piero
P
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects; D001552:Benzazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D006868:Hydrolysis; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007545:Isoproterenol / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects; D013237:Stereoisomerism; D014132:Trachea / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D001552:Benzazepines; D002317:Cardiovascular Agents; D007202:Indicators and Reagents; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D007545:Isoproterenol