Inhibition of human Na(v)1.5 sodium channels by strychnine and its analogs

Strychnine and brucine from the seeds of the plant Strychnos nux vomica have been shown to have interesting pharmacological effects on several neurotransmitter receptors. In this study, we have characterized the pharmacological properties of strychnine and its analogs on human Na_v1.5 channels to assess their potential therapeutic advantage in certain arrhythmias. Among the eight alkaloids, only strychnine and icajine exhibited inhibition potency on the Na_v1.5 channel with the half-maximum inhibition (IC₅₀) values of 83.1 μM and 104.6 μM, respectively. Structure–function analysis indicated that the increased bulky methoxy groups on the phenyl ring or the negatively charged oxygen atom may account for this lack of inhibition on the Na_v1.5 channel. Strychnine and icajine may bind to the channel by cation–π interactions. The substitution with a large side chain on the phenyl ring or the increased molecular volume may alter the optimized position for the compound close to the binding sites of the channel. Strychnine and icajine bind to the Na_v1.5 channel with a new mechanism that is different from TTX and local anesthetics. They bind to the outer vestibule of the channel pore with fast association and dissociation rates at resting state. Strychnine and icajine had little effect on steady-state fast inactivation but markedly shifted the slow inactivation of Na_v1.5 currents toward more hyperpolarized potentials. The property of icajine influencing slow-inactivated state of Na_v1.5 channel would be potential therapeutic advantages in certain arrhythmias.     

Design,Synthesis, and Antitumor Activity of 4-Halocolchicines and Their Pro-drugs Activated by Cathepsin B

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