Effects of new 4-aminopyridine derivatives on neuromuscular transmission and on smooth muscle contractility.
The effects of new 4-aminopyridine (4-AP) derivatives were investigated in the isolated mouse phrenic nerve-hemidiaphragm preparation under single impulse stimulation and tetanic conditions. The basic 4-AP structure was modified in position 3 on the pyridine nucleus by introducing different substituents. Results were compared to those obtained with 4-AP and 3,4-diaminopyridine. The compounds were tested for their antagonistic effect against calcium antagonists and botulinum toxin A. The effect on smooth muscle was investigated on the isolated guinea-pig ileum. Physico-chemical parameters of the test compounds were determined by the partition coefficient and ionization constant. Finally structure-activity relationship analysis revealed that the activity was highly related to lipophilicity and the steric volume. So far 4-AP itself provided the most advantageous molecular structure.
Berger
S G
SG
Institute of Pharmacology, University of Zurich, Switzerland.
Waser
P G
PG
Hofmann
A
A
D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003620:Dantrolene / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000294:innervation; D009469:Neuromuscular Junction / Q000187:drug effects*; D010791:Phrenic Nerve / Q000187:drug effects; D012132:Respiratory Muscles / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*; D014268:Trifluoperazine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D000631:Aminopyridines; D014268:Trifluoperazine; D014700:Verapamil; D001905:Botulinum Toxins; D003620:Dantrolene