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.