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4‐aminopyridine derivatives: A family of novel modulators of voltage‐dependent sodium channels
Author(s) -
Tang Lei,
Huger Francis P.,
Klein Joseph T.,
Davis Larry,
Martin Lawrence L.,
Shimshock Stephen,
Effland Richard C.,
Smith Craig P.,
Kongsamut Sathapana
Publication year - 1998
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199805)44:1<8::aid-ddr2>3.0.co;2-l
Subject(s) - batrachotoxin , chemistry , veratridine , aminopyridines , indole test , carbazole , amine gas treating , 4 aminopyridine , sodium channel , stereochemistry , sodium , pyrrole , heterocyclic amine , ring (chemistry) , medicinal chemistry , potassium channel , organic chemistry , biophysics , biology
Abstract 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. Drug Dev. Res. 44:8–13, 1998. © 1998 Wiley‐Liss, Inc.