Activation and blockade of the acetylcholine receptor-ion channel by the agonists (+)-anatoxin-a, the N-methyl derivative and the enantiomer.

The effects of (+)- and (-)-anatoxin-a (AnTX) and N-methylanatoxin (M-AnTX) on peripheral nicotinic ion channel activity were studied using high micromolar concentrations. Whereas (+)-AnTX is an effective agonist at nanomolar concentrations, (-)-AnTX and M-AnTX were effective at low micromolar concentrations. The binding of [3H]perhydrohistrionicotoxin to the nicotinic acetylcholine receptor-ion channel was stimulated by the above agonist concentrations, but [3H]perhydrohistrionicotoxin binding was inhibited at high micromolar concentrations of each of the toxins. In single channel recordings, these toxins exhibited ion channel blocking properties; the concentration- and voltage-dependent kinetics of each were essentially the same. In the case of (+)-AnTX, desensitization was also present at micromolar concentrations. These data show that ion channel blockade may be a property of many anatoxin-a analogs, and that in the particular case of analogs with low agonist potency, ion channel blockade may be a concomitant primary effect of the toxins. Stereospecificity and number of amine moieties did not influence the ion channel blocking characteristics in this series of molecules, although these factors strongly modified agonist potency.