Mechanism for antagonism of paraoxon by hemicholinium-3 analogues

In a newly synthesized series of DMAE analogues (bis-diethyl analogue of hemicholinium-3), selected chemicals (TL-402 = NAM-242 greater than JGC-VII-110) showed significant protection of mouse lethality after acute toxic doses of paraoxon (in vivo). DMAE and NAM-250 (like hemicholinium-3) showed minimal or no antagonism against paraoxon-induced toxicity in mice. Studies with DMAE analogues demonstrate weak anticholinesterase activity. The pattern for the neuromuscular inhibition of TL-402, NAM-242 and JGC-VII-110 is different from that of hemicholinium-3. LD50 studies identified compounds with less inherent toxicity (TL-402, NAM-242 and JGC-VII-110) and showed significant antagonism in contrast to DMAE and NAM-250. These chemicals (DMAE and NAM-250) are as toxic as the parent compound hemicholinium-3. All compounds in this series showed potent antinicotinic activity in different nicotinic-receptor preparations. The antinicotinic activity correlates with their action on the acetylcholine receptor-ion channel complex at frog neuromuscular junctions (in vitro). Electrophysiological studies demonstrate that the antinicotinic agents significantly depressed both the end plate current (EPC) amplitude and the time constant of decay (tau EPC) at the end plate of frog. In presence of paraoxon, voltage- and concentration-dependent shortening of tau EPC is observed which is more prominent than the decrease of the amplitude of EPC. The antinicotinic agents which showed significant antagonism of paraoxon both in vivo and in vitro (TL-402, NAM-242 and JGC-VII-110) also produced profound tetanic rundown after neurally or ionophoretically evoked EPC. These effects are voltage-dependent. The marked shortening of tau EPC, linear relationship between 1/tau vs DMAE analogue concentrations and potential-dependent tetanic rundown suggest that these analogues produce antagonism of paraoxon primarily by reducing end plate permeability by blocking nicotinic ACh-R associated ion channels in their open form. The antinicotinic activity of these agents is related to acetal or corresponding ether substitution.