[Antagonistic effect of 4-aminopyridine derivatives on dTc induced block].
A new muscle relaxant antagonist, 4-aminopyridine (4-AMP), has various problems related to its side effects. In order to obtain 4-AMP derivatives with less side effect and the same antagonizing effect on dTc block as that of 4-AMP, three types of derivatives were synthesized. They were 4-methylaminopyridine (4-MAMP), 4-dimethylaminopyridine (4-DAMP), and 4-trimethylaminopyridine (4-TAMP). For the purpose of studying their effects on neuromuscular junction, the antagonistic effects of the three derivatives on the dTc block were compared with those of 4-AMP, by using rat diaphragm preparation in vitro, and rat sciatic nerve tibialis anterior muscle preparation in vivo. These three derivatives exhibited earlier onset time compared with 4-AMP, but their efficacy was lower in terms of ED50 in vivo and in vitro. Also their duration of effect was shorter than 4-AMP. In particular, the ED50 of 4-DAMP was much larger (9 times that of 4-AMP), and its duration of effect was shorter (11 minutes), indicating that it is unsuitable as a practical antagonistic agent. ED50 of 4-TAMP was the closest to that of 4-AMP (three times that of 4-AMP), and it exhibited effects earlier than 4-AMP (one fourth that of 4-AMP), but was inferior in duration of effect (13 minutes). With respect to antagonistic effects, these three agents cannot be described as perfect, and development of new derivatives will be required.
Amaki
Y
Y
Koyama
T
T
Wada
T
T
Kobayashi
K
K
Futaki
R
R
D015761:4-Aminopyridine / Q000031:analogs & derivatives*; D000631:Aminopyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D008297:Male; D009469:Neuromuscular Junction / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D014403:Tubocurarine / Q000037:antagonists & inhibitors*
D000631:Aminopyridines; C061053:4-methylaminopyridine; C061054:4-trimethylaminopyridine; D015761:4-Aminopyridine; C003885:4-dimethylaminopyridine; D014403:Tubocurarine