Discovery and preclinical evaluation of novel dopamine partial agonists as antipsychotic agents

Abstract

Antagonism of DA D2 receptors is thought to be the primary molecular mechanism for the efficacy of existing antipsychotic agents. This efficacy is believed to arise from blockade of DA D2 receptors in the mesolimbic and prefrontal brain regions. However blockade of DA D2 receptors in the striatum and caudate is thought to be responsible for the severe side effects associated with antipsychotic therapy including EPS and TD. Neurons that synthesize and release DA have DA autoreceptors on their presynpatic terminals and cell bodies. Stimulation of these autoreceptors by DA results in a negative feedback signal attenuating the synthesis and release of DA from these neurons. It has been hypothesized that partial agonists selective for DA autoreceptors could inhibit DA neurotransmission and therefore have antipsychotic efficacy. This review details the structure-activity relationships of DA partial agonists selective for DA D2 autoreceptors. Compounds having D2 and D3 affinity or D2 and 5-HT1A activity are also discussed. Compounds with the appropriate level of partial agonist activity were shown to have better efficacy/side effect profiles in primate models than standard DA D2 antagonists.