Antiarrhythmic activity of the local anaesthetic fomocaine and some of its analogues.
A series of fomocaine (N-[3-(4-phenoxymethylphenyl)propyl] morpholine hydrochloride) derivatives modified e.g. in the basic center and/or in the molecular moiety linking the two phenyl rings were investigated for antiarrhythmic activity in vitro and in vivo. Propafenone, quinidine, lidocaine, and fomocaine served as reference drugs throughout all experiments. In the in vitro experiments on guinea pig atrial preparations, the prolongation of the functional refractory period (FRP) and the reduction of the maximal driving frequency (MDF) were both taken as a measure of antiarrhythmic activity. Several fomocaine derivatives proved to be significantly more active in the in vitro assays than the reference drugs fomocaine, lidocaine or quinidine. Usually, the compounds containing a piperidine or a hexamethyleneimino ring system as a basic center exerted greater effects on FRP and MDF than the analogues containing a morpholine ring. Besides their effects on FRP and MDF, all drugs investigated produced negative inotropic responses in isolated guinea pig atria. The magnitude of this effect usually correlated well with the extent of FRP prolongation or MDF reduction. Based on the results of the in vitro experiments, some of the most active fomocaine derivatives were also tested for their ability to prevent aconitine-induced arrhythmias in the anaesthetized rat. While fomocaine itself was inactive, two fomocaine analogues containing an -O(CH2)3- chain linking the two phenyl rings showed pronounced antiarryhtmic activity in this in vivo preparation. LD50 determinations in mice revealed that these two agents show a lower acute toxicity than lidocaine and propafenone while being somewhat more toxic than quinidine and fomocaine.
Bräunig
B
B
Department of Pharmacology, Faculty of Biochemistry, Pharmacy and Food Chemistry, Johann Wolfgang Goethe-University, Frankfurt/Main, Fed. Rep. of Germany.
Busch
A E
AE
Mutschler
E
E
Wess
J
J
Oelschläger
H
H
D000157:Aconitine / Q000494:pharmacology; D000758:Anesthesia; D000779:Anesthetics, Local / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000889:Anti-Arrhythmia Agents; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D010647:Phenyl Ethers / Q000494:pharmacology* / Q000633:toxicity; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
D000779:Anesthetics, Local; D000889:Anti-Arrhythmia Agents; D010647:Phenyl Ethers; C100275:fomocain; D000157:Aconitine