4-aminopyridine derivatives: A family of novel modulators of voltage-dependent sodium channels

The interactions of a family of aminopyridine derivatives with Site II of the voltage-dependent sodium channel were examined by measuring the ability of these compounds to inhibit [³H]batrachotoxin binding and veratridine-induced increases in [Ca²⁺]_i. Aminopyridines substituted with indole, carbazole, and pyrrole rings were evaluated. All compounds that had an aromatic ring linked to the amine group of 4-aminopyridine showed positive results in both assays. For example, the most potent compound, besipirdine (N-(n-propyl)-N-(4-pyridinyl)-1H-indol-1-amine), had IC₅₀ values of 5 μM and 23.8 μM in the two assays, respectively. Small substitutions on either the aromatic ring or on 4-aminopyridine did not substantially change their potencies. Indoles linked to the amino group of 2- and 3-aminopyridine also showed positive results. These results indicate that aminopyridine derivatives substituted with an aromatic ring on the amino nitrogen are inhibitors of voltage-dependent sodium channels. Drug Dev. Res. 44:8–13, 1998. © 1998 Wiley-Liss, Inc.