[New GABA-A receptor blockers: attempts to find more powerful clozapine-like selective GABA antagonists]

Because clozapine and a number of other antipsychotic, as well as antidepressant drugs selectively block subsets of GABAA receptors, we have routinely screened 1100 compounds since 1983 for GABA antagonistic effects on 35S-TBPS binding, with a view to finding more potent clozapine-like selective GABAA receptor blockers. About 225 GABA antagonists were identified. Among compounds not previously published, four groups of tricyclic compounds (phenothiazines, phenoxazines, acridines and phenazines) contained GABAA receptor blockers, with acridines and oxidized phenothiazines in general being the most potent. Other active groups include cocaine derivatives, xanthines, indoles and phenethylamine derivatives. A large group of miscellaneous structures includes all known GABAA receptor blockers, as well as some antihistamines, antitussives, antimalarial/antiprotozoals, potential antidepressant, and a large non-therapeutic category consisting of diverse chemical structures. The amino steroid R5135 remains the most potent GABAA receptor blocker by far (EC50 = 5.7 nM, delta Bopt = 130%), and is non-aromatic. Pitrazepin, the next-most potent GABAA receptor blocker (EC50 = 360 nM), also fully reverses the inhibitory effect of 1 microM GABA on 35S-TBPS binding, but is 63-fold less potent than R5135. Appropriately positioned amidino groups, ring (aromatic) nitrogen, ether and keto groups can contribute to the potency of GABAA receptor blockade. Clozapine-like selective GABAA receptor blockers with EC50 values in the low nanomolar range remain to be identified. Such compounds may have potent antipsychotic effects.