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

✍ Scribed by Lei Tang; Francis P. Huger; Joseph T. Klein; Larry Davis; Lawrence L. Martin; Stephen Shimshock; Richard C. Effland; Craig P. Smith; Sathapana Kongsamut

• Book ID: 101265639
• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 105 KB
• Volume: 44
• Category: Article
• ISSN: 0272-4391
• DOI: 10.1002/(sici)1098-2299(199805)44:1<8::aid-ddr2>3.0.co;2-l

✦ Synopsis

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 [ 3 H]batrachotoxin binding and veratridine-induced increases in [Ca 2+ ] 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 IC 50 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.