[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.