Vaninolol: a new selective beta 1-adrenoceptor antagonist derived from vanillin.
The beta-adrenoceptor blocking properties of vaninolol ((+/-)4-[4'-(2-hydroxy-3-tert-butyl-aminopropoxy)-3'-methoxyphenyl]- 3-buten-2-one), derived from vanillin, were first investigated under in vivo and in vitro conditions. Vaninolol (0.1, 0.5, 1.0 mg/kg, i.v.), as well as propranolol, produced a dose-dependent bradycardia response and a sustained pressor action in urethane-anesthetized normotensive rats. Vaninolol inhibited the tachycardia effects induced by (-)isoproterenol, but had no blocking effect on the arterial pressor responses induced by phenylephrine. These findings suggested that vaninolol possessed beta-adrenergic blocking activity, but was without alpha-adrenergic blocking activity. In isolated guinea-pig tissues, vaninolol antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol suggested that vaninolol was a beta-adrenoceptor competitive antagonist. The effect of vaninolol was more potent on the atria than on tracheal tissues, indicating it had some beta 1-adrenoceptor selectivity. On the other hand, the order of the hydrophilicity was atenolol >> vaninolol > propranolol. In addition, vaninolol had a mild direct cardiac depression at high concentrations and was without intrinsic sympathomimetic activity (ISA). Furthermore, binding characteristics of vaninolol and other beta-adrenoceptor antagonists were evaluated in [3H]dihydroalprenolol binding to guinea-pig ventricular membranes. The order of potency of beta-adrenoceptor antagonists in competing for the binding sites was (-)propranolol >> vaninolol > or = atenolol. In conclusion, vaninolol was found to be a selective beta 1-adrenoceptor antagonist with relatively low lipophilicity in comparison with propranolol, devoid of ISA, and had a mild myocardial depressant effect.
Wu
B N
BN
Department of Pharmacology, Kaohsiung Medical College, Taiwan, Republic of China.
Hwang
T L
TL
Liao
C F
CF
Chen
I J
IJ
D058671:Adrenergic beta-1 Receptor Antagonists; D000818:Animals; D001547:Benzaldehydes / Q000737:chemistry*; D001794:Blood Pressure / Q000187:drug effects; D002074:Butanones / Q000302:isolation & purification* / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D011412:Propanolamines / Q000302:isolation & purification* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013566:Sympathomimetics / Q000494:pharmacology
D058671:Adrenergic beta-1 Receptor Antagonists; D001547:Benzaldehydes; D002074:Butanones; D011412:Propanolamines; D013566:Sympathomimetics; C088562:vaninolol; C100058:vanillin