Synthesis and Structure-Activity Relationships of Series of Aminopyridazine Derivatives of γ-Aminobutyric Acid Acting as Selective GABA-A Antagonists

Article abstract of DOI:10.1021/jm00385a003

We have recently shown that an aryloaminopyridazine derivarive of GABA, SR 95103 <2-(3-carboxypropyl)-3-amino-4-methyl-6-phenylpyridazinium chloride>, is a selective and competitive GABA-A receptor antagonist.In order to further explore the structural requirements for GABA receptor affinity, we synthesized a series of 38 compounds by attaching various pyridazinic structures to GABA or GABA-like side chains.Most of the compounds displaced <3H>GABA from rat brain membranes.All the active compounds antagonized the GABA-elicited enhancement of <3H>diazepam binding, strongly suggesting that all these compounds are GABA-A receptor antagonists.None of the compounds that displaced <3H>GABA from rat brain membranes interacted with other GABA recognition sites (GABA-B receptor, GABA uptake binding site, glutamate decarboxylase, GABA-transaminase).They did not interact with the Cl^- ionophore associated with the GABA-A receptor and did not interact with the benzodiazepine, strychnine, and glutamate binding sites.Thus these compounds appear to be specific GABA-A receptor antagonists.In terms of structure-activity, it can be concluded that a GABA moiety bearing a positive charge is necessary for optimal GABA-A receptor recognition.Additional binding sites are tolerated only if they are part of a charge-delocalized amidinic or guanidinic system.If this delocalization is achieved by linking a butyric acid moiety to the N(2) nitrogen of a 3-aminopyridazine, GABA-antagonistic character is produced.The highest potency (ca.250 times bicuculline) was observed when an aromatic ? system, bearing electron-donating substituents, was present on the 6-position of the pyridazine ring.