Dopamine autoreceptor agonists as potential antipsychotics. 1. (Aminoalkoxy)anilines

The synthesis and pharmacological properties of a novel type of [(arylpiperazinyl)alkoxy]anilines with dopaminergic properties are described. One of these compounds, 3-[3-(4-phenyl-1-piperazinyl)propoxy]benzenamine (4c), has been identified as a selective dopamine (DA) autoreceptor agonist in tests that include [3H]haloperidol binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. In addition, 4c possesses good oral activity in the Sidman conditioned avoidance test in squirrel monkeys, which is indicative of antipsychotic activity. In a primate model, 4c was found to lack the liability for extrapyramidal side effects usually associated with antipsychotic drugs.