[New beta-sympatholytic agents. Synthesis and pharmacological activity of isomeric benzthiazole and benzoxazole derivates (author's transl)].
The synthesis and comparative pharmacological studies concerning structure-activity relationship of new benzothiazole, benzisothiazole, benzoxazole, and benisoxazole derivatives with beta-sympatholytic activity are reported. Most of the 4-benzisothiazole derivatives studied strongly act on cardiac beta 1-receptors in rats in situ (2.6-8.3 times propranolol). On the other hand derivatives of 4-benzisoxazole and 5-benzisothiazole are less potent. A strong decrease in activity was observed going from the benzisothiazoles and benzisoxazoles to the isomeric benzthiazoles and benzoxazoles. The active substances also block vascular beta 2-receptors. In the most cases they have little intrinsic adrenergic activity. The observed tendency concerning beta 1-selectivity in rats could not be confirmed in cats. The most potent 4-benzisothiazole derivatives in rats show also - beside some minor differences - very good beta-sympatholytic activity in cats after i.v. as well as after i.d. administration. Similar to the results in rats and cats the 4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole (LU 24329) was found to possess a high activity in conscious dogs by oral or i.v. application. Both in dogs (i.v.) and in isolated perfused guinea pig hearts LU 24329 is eleven times more active than propranolol in blocking beta 1-receptors. A negative inotropic effect as an expression of non-specific membrane-stabilizing action of LU 24329 is also demonstrated in guinea pig hearts. The effective concentration is 4650 times higher than that effective on beta 1-adrenoceptors. The active compounds have a moderate acute toxicity. The LD50 values in mice after i.p. administration are ranging from 55-174% of the propranolol toxicity.
D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis*; D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002415:Cats; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007536:Isomerism; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D001583:Benzoxazoles; D013844:Thiazoles
Neue beta-Sympatholytika: Synthesen und pharmakologische Wirkung isomerer Benzthiazol- und Benzoxazol-Derivate.