3-[[(4-Aryl-1-piperazinyl)alkyl]cyclohexyl]-1H-indoles as dopamine D2 partial agonists and autoreceptor agonists

A series of arylpiperazines and tetrahydropyridines joined to indoles by semirigid cycloalkyl spacers were prepared. Target compounds were studied for their ability to bind to the DA D2 receptor in vitro and to inhibit dopamine synthesis and spontaneous locomotor activity in rats. Effects of tether length and relative stereochemistry were assessed for a series of 2-pyridylpiperazines. The cyclohexylethyl spacer was found to be the most active in the series. Further studies explored effects of changes in the arylpiperazine and indole portions of the molecule. From these studies trans-2-[[4-(1H-3-indolyl)cyclohexyl]ethyl]-4- (2-pyridinyl)piperazine (30a) was selected for further evaluation. It was characterized as a partial agonist of DA D2 receptors in vitro and caused decreases in dopamine synthesis and release as well as dopamine neuronal firing. Compound 30a was shown to be devoid of behavioral effects associated with postsynaptic DA D2 receptor activation. Furthermore, compound 30a was shown both to decrease DA synthesis and to inhibit Sidman avoidance responding in squirrel monkeys. These findings suggest that DA D2 partial agonists with the appropriate level of intrinsic activity can act to decrease dopamine synthesis and release and may have potential utility as antipsychotic agents.