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In vivo pharmacology of BIIR 561 CL, a novel combined antagonist of AMPA receptors and voltage‐dependent Na + channels
Author(s) -
Wienrich M,
Brenner M,
Löscher W,
Palluk R,
Pieper M,
Potschka H,
Weiser T
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704132
Subject(s) - ampa receptor , antagonist , in vivo , pharmacology , chemistry , biophysics , receptor , medicine , glutamate receptor , biochemistry , biology , microbiology and biotechnology
Glutamate receptors of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) subtype and voltage‐gated Na + channels are associated with diseases of the central nervous system characterized by neuronal over‐excitation as in epilepsy or cerebral ischaemia. In animal models, AMPA receptor antagonists and Na + channel blockers provide protection in these conditions. Dimethyl‐{2‐[2‐(3‐phenyl‐[1,2,4]oxadiazol‐5‐yl)‐phenoxyl]‐ethyl}‐amine hydrochloride (BIIR 561 CL) combines both, AMPA receptor – and Na + channel blocking properties in one molecule. Here, BIIR 561 CL was investigated in vivo . BIIR 561 CL protected mice against AMPA‐induced toxicity with an ED 50 value of 4.5 mg kg −1 following subcutaneous (s.c.) administration. A 0.1% solution of BIIR 561 CL provided local anaesthesia in the corneal reflex test in rabbits. In mice, the compound prevented tonic seizures in the maximal electroshock (MES) model with an ED 50 value of 3.0 mg kg −1 s.c. In amygdala‐kindled rats, BIIR 561 CL inhibited seizures at doses of 3 and 11 mg kg −1 following intraperitoneal (i.p.) injection. The data show that the combination of blocking AMPA receptor‐ and voltage‐gated Na + channels in one molecule induces effective protection in animal models of neuronal over‐excitation.British Journal of Pharmacology (2001) 133 , 789–796; doi: 10.1038/sj.bjp.0704132