PUMILIOTOXIN-C AND SYNTHETIC ANALOGS - A NEW CLASS OF NICOTINIC ANTAGONISTS

  • 1 January 1982
    • journal article
    • research article
    • Vol. 22  (3) , 565-573
Abstract
Pumiliotoxin-C (PTX-CI), a cis-decahydroquinoline alkaloid, and synthetic analogs inhibited directly and indirectly elicited twitches in rat phrenic nerve diaphragm preparations. At 40 .mu.M the most potent analog, 2,5-di-n-propyl-cis-decahydroquinoline (PTX-CII), reversibly blocked the indirectly elicited twitch and markedly depressed the amplitude of end-plate potentials and miniature end-plate potentials without affecting muscle membrane potential. PTX-CII did not depress the directly elicited twitch in diaphragm muscle treated with .alpha.-bungarotoxin. At 40 .mu.M, the compound blocked extrajunctional acetylcholine (ACh) sensitivity in chronically denervated soleus muscle of the rat. The peak amplitude of the end-plate current in frog sartorius muscle was depressed by PTX-CII at both positive and negative membrane potentials. Nonlinearity in the current-voltage relationship appeared at membrane potentials greater than -100 mV with concentrations of PTX-CII from 2.5-7.5 .mu.M. The decay phase of the end-plate current was shifted to lower values such that it decayed faster at all membrane potentials but retained voltage sensitivity. PTX-CII, the most potent of the analogs, inhibited binding of [3H]perhydrohistrionicotoxin to Torpedo electroplax membranes with an IC50 [median inhibitory concentration] value of 1.5 .mu.M in the absence of carbamylcholine (Carb) and 0.1 .mu.M in the presence of Carb. The other analogs were less potent, but all showed higher affinities in the presence of Carb. PTX-CI, PTX-CII, and PTC-CIII had no effect on the binding of [125I].alpha.-bungarotoxin to ACh receptors in Torpedo membranes while slightly enhancing the binding of [3H]ACh, whereas PTX-CIV gave slight inhibition of both receptor ligands at concentrations > 10 .mu.M. The pumiliotoxin-C class of alkaloids therefore appears to block neuromuscular transmission primarily via interactions with sites associated with the ion channel controlled by the ACh receptor.