Neuromuscular blocking action of two hemicholinium-3 analogs.
Two hemicholinium-3 (HC-3) analogs (NAM-204 and NAM-224) in which the C = O moiety was reduced to -CH2 and 2- or 3-CH3 substitution on the piperidine ring were demonstrated to produce a different type of neuromuscular inhibition than that induced by HC-3. The neuromuscular blocking activity was tested in several different preparations and it was shown that these compounds are potent, short-acting, and was reversed by neostigmine but not by choline. Although these compounds possess weak anticholinesterase activity, significant alterations of blood pressure and heart rate are absent. Miniature end-plate potentials' amplitude were found to be diminished by these compounds with some alteration of frequency. In voltage-clamped frog sartorius muscle NAM-224 and NAM-204 decreased amplitude of miniature end-plate current (mepcs) and accelerated the time constant of mepc decay in a concentration-dependent manner, without altering the single exponential nature of mepc decay. NAM-204 and NAM-224 at high concentrations also produced a voltage- and concentration-dependent non-linearity in current/voltage relationships, especially at more negative membrane potentials. Hence, these pharmacological and electrophysiological studies indicate NAM-224 and NAM-204 have significant activity at both pre- and post-junctional sites and their post-junctional blocking activity results from blocking ACh receptor/ion channel complex.
Bhattacharyya
B
B
Department of Anesthesia, College of Medicine, University of Iowa, Iowa City 52242.
Sokoll
M D
MD
Cannon
J G
JG
Long
J P
JP
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D002417:Cattle; D002800:Cholinesterase Inhibitors; D004594:Electrophysiology; D006426:Hemicholinium 3 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008839:Microelectrodes; D009045:Motor Endplate / Q000187:drug effects; D009466:Neuromuscular Blocking Agents; D009469:Neuromuscular Junction / Q000187:drug effects; D011817:Rabbits; D011894:Rana pipiens; D051381:Rats; D011919:Rats, Inbred Strains; D009435:Synaptic Transmission / Q000187:drug effects; D014403:Tubocurarine / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D009466:Neuromuscular Blocking Agents; D006426:Hemicholinium 3; D014403:Tubocurarine