Novel state-dependent voltage-gated sodium channel modulators, based on marine alkaloids from Agelas sponges

Clathrodin, alkaloid isolated from Agelas sponges, was reported in 1995 as a voltage-gated sodium channel modulator. Here we describe the design and synthesis of conformationally restricted clathrodin analogues incorporating the 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine moiety and evaluation of their modulatory activities on human voltage-gated sodium channel isoforms Na(v)1.3, Na(v)1.4 and Na(v)1.7, as well as their selectivity against cardiac isoform Na(v)1.5. Compounds were shown to act as state-dependent modulators of Na(v)1.3, Na(v)1.4 and Na(v)1.7 with IC₅₀ values in the lower micromolar range for the open-inactivated state of the channels. Preliminary structure-activity relationship studies have revealed the importance of hydrophobic interactions for binding to all three tested isoforms. Compound 4e with IC₅₀ value of 8 μM against Na(v)1.4 represents a novel selective state-dependent Na(v)1.4 channel modulator.