An arylaminopyridazine derivative of gamma-aminobutyric acid (GABA) is a selective and competitive antagonist at the GABAA receptor site.

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Abstract
In view of finding a new .gamma.-aminobutyric acid (GABA) receptor ligand and arylaminopyridazine derivative of GABA, SR 95103 [2-(carboxy-3''-propyl)-3-amino-4-methyl-6-phenylpyridazinium chloride] was synthesized. SR 95103 displaced [3H]GABA from rat brain membranes with an apparent Ki of 2.2 .mu.M and a Hill number near 1.0. SR 95103 (1-100 .mu.M) antagonized the GABA-mediated enhancement of [3H]diazepam binding in a concentration-dependent manner without affecting [3H]diazepam binding per se. SR 95103 competitively antagonized GABA-induced membrane depolarization in rat spinal ganglia. In all these experiments, the potency of SR 95103 was close to that of bicuculline. SR 95103 (100 .mu.M) did not interact with a variety of central receptors-in particular the GABAB, the strychnine and the Glu receptors-did not inhibit Na+-dependent synaptosomal GABA uptake, and did not affect GABA-transaminase and Glu decarboxylase activities. The i.p. administered SR 95103 elicited clonicotonic seizures in mice (ED50 = 180 mg/kg). On the basis of these results it is postulated that SR 95103 is a competitive antagonist of GABA at the GABAA receptor site. In addition to being an interesting lead structure for the search of GABA ligands, SR 95103 could also be a useful tool to investigate GABA receptor subtypes because it is freely soluble in water and chemically stable.