New 5-aminoacyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-ones with antiarrhythmic activity.
A series of new 5-substituted tricyclic 5,10-dihydro-11H-dibenzo[b,e][1,4]-diazepin-11-ones was identified as potential antiarrhythmic agents against bradyarrhythmias [1, 2]. The in vitro and in vivo interactions of the compounds with muscarinic receptors and the antiarrhythmic activity were examined. In receptor binding studies some derivatives showed a high affinity to the cardiac M2 receptor (Ki 10 nmol/l), an equal or smaller affinity to cortical M1 receptor and a lower affinity to the glandular M3 binding site. Functional experiments showed the derivatives as competitive antagonists with high affinity to the cardiac and smaller affinity to the intestinal muscarinic receptor. In vivo experiments correspond with the M2 selectivity. First the vagal or agonist-induced bradycardia was inhibited in rats and guinea pigs while the McNA-343 induced increase of blood pressure, methacholine-induced bronchi and bladder constriction as well as the salivation were inhibited only at higher doses. In conscious cats the tachycardia was examined in comparison with pupillomotoricity. The effect duration and the therapeutical range were determined in comparison to the M2 selective blocking agent AF-DX116. The antiarrhythmic activity was examined compared to quinidine sulfate in CaCl2-arrhythmia of rats, in atrial fibrillation and atrial flutter in dogs according to Scherf [2] and in electric induced atrial fibrillation under vagal stimulation in cats. In the atrial arrhythmias the derivatives are clearly longer effective than quinidine sulfate. The antiischemic activity was examined in the two-stages coronary ligature in dogs according to Harris. The long-running regularization of ectopies (about 2 h after i.v. injection) occurred without decrease of the heart rate, an effect particularly convenient to therapy of bradycardic dysrhythmias.
Poppe
H
H
Department of Chemical Research 1, Corporate R & D, Moscow, Russia.
Kaverina
N V
NV
Lyskovzev
V V
VV
Egerland
U
U
Sauer
W
W
Lichoscherstow
A
A
Rüger
C
C
Skoldinow
A
A
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects; D002415:Cats; D018680:Cholinergic Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009928:Organ Specificity; D010276:Parasympatholytics / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011680:Pupil / Q000187:drug effects; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects; D012472:Salivation / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D018680:Cholinergic Antagonists; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; D001569:Benzodiazepines; D010890:Pirenzepine; C048593:otenzepad