Interaction of analogs of histrionicotoxin with the acetylcholine receptor ionic channel complex and membrane excitability.

The effects of the four N-benzylazaspiro analogs of histrionicotoxin, which are without the two side-chains typical of histrionicotoxin, were studied on the ionic channels of electrically excitable membrane and the nicotinic acetylcholine receptors in frog sartorius muscles. Each analog reversibly blocked the indirectly elicited twitch and potentiated the directly elicited twitch in a concentration-dependent manner. The analogs decreased the amplitude and rate of rise and prolonged the falling phase of the directly elicited action potential and blocked delayed rectification suggesting blockade of sodium and potassium conductances. All of the analogs caused a concentration- and voltage-dependent depression of the peak end-plate current amplitude and induced nonlinearity but no hysteresis or time dependency in the current-voltage relationship. The marked shortening of the time constant of end-plate current decay produced by the analogs was concentration-dependent. The relationship between the time constant of end-plate current decay and membrane potential remained a single exponential function of time despite the marked shortening of the decay phase and loss of voltage dependence. The effect of the analogs on miniature end-plate current was identical to that on end-plate current. Single channel conductance was unaffected by the analogs, but the single channel lifetime was shortened. The marked shortening of the time constant of the end-plate current decay and single channel lifetime plus linear relationship between reciprocal of the time constant of decay and analog concentrations strongly suggest that the analogs interact with the ionic channels of the nicotinic acetylcholine receptor in their open conformation.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenylthioalkylamines in experimental tumor treatment in mice.

Two phenylthioalkylamines, phenylthioethylamine (PTEA) and phenylthiopropylamine (PTPA), were prepared and tested for cytotoxicity in vitro and as antitumor agents in (C57BL X DBA/2)F1 (BDF1) mice. Low concentrations of PTEA (median effective concentrations of 8.0, 12.0, and 1.3 micrograms PTEA/ml) inhibited the growth of P388 murine lymphoma, L1210 leukemia, and B16 melanoma cells in culture. PTPA was more effective; concentrations of 0.80, 0.56, and 0.35 micrograms PTPA/ml inhibited the growth of P388, L1210, and B16 in vitro by 50%. PTEA and PTPA treatment increased survival times in BDF1 mice bearing the P388 lymphoma, L1210 leukemia, B16 melanoma, and Lewis lung tumors. Multiple daily administrations of the test compounds were more effective than single daily injections in increasing the life-span in mice bearing the P388 lymphoma and B16 melanoma. Both PTEA and PTPA inhibited the enzyme copper-zinc superoxide dismutase.