A study of the novel synthetic analog (+/-)- depentylperhydrohistrionicotoxin on the nicotinic receptor-ion channel complex

MA Maleque, K Takahashi, B Witkop, A Brossi and EX Albuquerque

(+/-)-Depentylperhydrohistrionicotoxin [(+/-)-depentyl-H12-HTX] is a synthetic analog of perhydrohistrionicotoxin (H12-HTX) that lacks the 5- carbon side chain. Recent studies with N-benzylazaspiro analogs of histrionicotoxin (HTX) in which both side chains are removed revealed that this alteration restricted the action of the compounds on the acetylcholine receptor-ionic channel complex (AChR) to an open channel blockade. Thus, an important question was raised as to the role of the side chains in affecting the interaction of these inhibitors with the AChR. In addition, the effect of (+/-)-depentyl-H12-HTX on membrane excitability was investigated. (+/-)-Depentyl-H12-HTX blocked the indirectly elicited twitch without affecting the directly elicited twitch. It decreased the amplitude and rate of rise and prolonged the falling phase of the action potential and blocked delayed rectification suggestive of blockade of sodium and potassium conductances. However, its effects on sodium and potassium conductances were less marked than those of HTX. It decreased the peak amplitude of the end-plate currents (EPCs) and accelerated the decay time constant of EPCs (tau EPC) in a concentration-dependent manner. The analog also induced voltage- and time-dependent nonlinearity in the current-voltage relationship of EPCs. Despite marked shortening of tau EPC, the decay phase of the EPC remained a single exponential function of time. Single channel conductance was unaffected by the analog, but the single channel lifetime was shortened. The voltage- and time-dependent effects of the analog that occurred without prior activation of AChR suggest reaction with the ionic channel in its closed conformation.

Volume 230, Issue 3, pp. 619-626, 09/01/1984
Copyright © 1984 by American Society for Pharmacology and Experimental Therapeutics