ABSTRACT
The antiarrhythmic activity of 20 derivatives of dibenzazepine (the effects on the maximal effective rabbit heart auricle contraction rate, aconitine-induced arrhythmia in rats under or without anesthesia) was studied. It was shown that the most active compounds are those with carbethoxyamine group in position 3 in combination with dimethylamino- or diethylamino-acetyl groups in position 5 of dibenzazepine ring. 5-dimethyl-aminoacetyl-10,11-dihydro-5H-dibenz b, f azepine (GS-015, bonnecor) was selected for the further detailed investigation.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Dibenzazepines/pharmacology , Aconitine , Animals , Anti-Arrhythmia Agents/therapeutic use , Anti-Arrhythmia Agents/toxicity , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/drug therapy , Dibenzazepines/therapeutic use , Dibenzazepines/toxicity , Drug Evaluation, Preclinical , Heart Rate/drug effects , In Vitro Techniques , Lethal Dose 50 , Rabbits , Rats , Structure-Activity RelationshipABSTRACT
The antiarrhythmic and local anesthetic effects of 4 metabolites (G 491, ABD 19-200, ABD 19-199, ABD 19-205) of a new antiarrhythmic drug bonnecor (GS-015) were studied on the models of arrhythmias induced by aconitine (rats), barium chloride (rabbits), electrical fibrillation (cats), ouabain (dogs) as well as surface anesthesia (rabbit cornea). The side effects on the cardiovascular system were investigated on anesthetized cats. As compared with the original compound (bonnecor) metabolites G 491 and ABD 19-200 on different test models exhibited the action which on the antiarrhythmic terms was 2-14 times less weak than that of bonnecor but the metabolites were less toxic. Metabolites ABD 19-199 and ABD 19-205 reach the degree of effectiveness of bonnecor but their toxicity is higher. It follows from the above that the beneficial effect of bonnecor is not achieved by its metabolites.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Dibenzazepines/pharmacology , Animals , Anti-Arrhythmia Agents/metabolism , Anti-Arrhythmia Agents/toxicity , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/drug therapy , Dibenzazepines/metabolism , Dibenzazepines/toxicity , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Rabbits , Rats , Ventricular Fibrillation/drug therapy , Ventricular Fibrillation/etiologyABSTRACT
The comparative study of the psychotropic activity of new acyl derivatives of dibenzazepine and phenothiazine--bonnecor (chlorhydrate 3-carbethoxyamino-5(dimethylaminoacetyl) dibenzazepine and ethacizine (chlorhydrate 2-carbethoxyamino-10-(beta-diethyl-aminopropionyl)phenothiazine)--in the experiments on small laboratory animals showed the presence of the antidepressive, anxiolytic, antiamnesic and antihypoxic effects. The drugs exerted the psychotropic effects at administration in the doses exceeding those which influence the cardiovascular system. By the degree of the anxiolytic action bonnecor and ethacizine are inferior to diazepam, are as potent as trioxasine and are superior to meprobamat. The noted psychotropic action by its character and degree can serve as a beneficial supplement to the spectrum of the pharmacological activity of the studied compounds.
