Pharmacological properties of an extremely selective beta 1-adrenoceptor antagonist, 2-[4-[3-(tert-Butylamino)-2-hydroxypropoxy] phenyl]-3-methyl-6-methoxy-4(3H)-quinazolinone [+/-)HX-CH 44 BS).
2-[4-[3-(tert-Butylamino)-2-hydroxypropoxy] phenyl]-3-methyl-6-methoxy-4(3H)-quinazolinone (+/-)HX-CH 44 BS) is a new beta 1-selective adrenoceptor antagonist. Affinity for beta 1-adrenoceptors was determined in isolated guinea-pig papillary muscle (pA2 = 7.4), in isoprenaline-stimulated guinea-pig cardiac adenylate cyclase (pA2 = 7.3) and in receptor binding experiments with rat heart membranes (pKi = 8.0). Due to a direct relaxing action of (+/-)HX-CH 44 in smooth muscles its beta 2-affinity could only be estimated from receptor binding experiments (pKi = 5.0). (+/-)HX-CH 44 BS shows an extremely high beta 1/beta 2-affinity ratio of about 800 and therefore appears to be much more selective than atenolol or metoprolol (beta 1/beta 2 = 10-50). In contrast to propranolol or atenolol, (+/-)HX-CH 44 hardly antagonized bronchodilation induced by i.v. isoproterenol in anaesthetized guinea-pigs in vivo. Furthermore, cardiac actions of the beta 1-selective agonist norepinephrine in cats in vivo were competitively antagonized by (+/-)HX-CH 44 whereas inotropic and chronotropic effects of the non-selective beta-agonist epinephrine were not. This phenomenon may be explained by the mixed population of beta 1-and beta 2-adrenoceptors in cat heart and by the high beta 1-selectivity of (+/-)HX-CH 44.
Daemmgen
J W
JW
Engelhardt
G
G
Pelzer
H
H
D000109:Acetylcholine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D002121:Calcium Channel Blockers; D002415:Cats; D003331:Coronary Vessels / Q000187:drug effects; D004837:Epinephrine / Q000037:antagonists & inhibitors; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000037:antagonists & inhibitors; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D010210:Papillary Muscles / Q000187:drug effects; D011412:Propanolamines / Q000378:metabolism / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D052999:Quinazolinones; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013552:Swine; D014132:Trachea / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D011412:Propanolamines; D052999:Quinazolinones; D011943:Receptors, Adrenergic, beta; C045066:HX-CH 44BS; D011433:Propranolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D000109:Acetylcholine; D009638:Norepinephrine; D004837:Epinephrine