Electrophysiological study of SR 42641, a novel aminopyridazine derivative of GABA: antagonist properties and receptor selectivity of GABAA versus GABAB responses

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Abstract
1. A new arylamino-pyridazine .gamma.-aminobutyric acid (GABA) derivative, SR 42641, has been tested for its ability to antagonize the actions of GABA on mammalian sensory neurones. 2. SR 42641 and bicuculline reversibly decreased GABAA-induced depolarizations and currents recorded intracellularly from dorsal root ganglion neurones (DRG). Dose-response curves were shifted to the right in a parallel fashion. KB values (determined under voltage clamp conditions) were respectively 0.12 .+-. 0.05 and 0.38 .+-. 0.08 .mu.M. Similar values were obtained with current clamp recording conditions. 3. The study of the GABA-induced Cl- current under voltage-clamp conditions did not show any voltage-dependency of the antagonist effect of SR 42641. 4. In nodose ganglion neurones, SR 42641 (0.4-4.5 .mu.M) did not alter the (-)-baclofen-induced shortening of the calcium component of action potentials. At concentrations higher than 10 .mu.M, SR 42641 itself prolonged calcium-dependent action potentials. 5. Patch-clamp recordings from DRG cultured neurones indicated that SR 42641 did not affect the calcium current responsible for sustained calcium entry into cells. 6. We conclude that SR 42641 is a potent competitive GABA antagonist, specific for the GABAA receptor. It does not act at the level of the chloride ionophore.