PNU-99194A: A preferential dopamine D3 receptor antagonist

Abstract

We have described the medicinal chemistry leading to the discovery of PNU-99194A, a preferential dopamine D3 receptor antagonist. In addition, we have presented the in vitro and in vivo characterization of this unique compound. PNU-99194A binds with nanomolar potency to the D3 receptor and displays a 20-fold lower potency at the D2 receptor in vitro. In vivo studies suggest that this compound produces behavioral activation over a wide dose range, but no sedation or catalepsy. Although PNU-99194A produces behavioral activation, it does not possess strong positive reinforcing properties. Thus, the profile of this compound is very different from that of the D2-preferring antagonists such as haloperidol (Table 2). These findings, in combination with data on c-fos expression and 2-DG utilization in the brain, indicate that compounds with this profile may prove to be antipsychotic with particular efficacy against negative symptoms and cognitive deficits, and are devoid of extrapyramidal side effects. Finally, PNU-99194A has power to be a valuable tool for the investigation of the functional role of the D3 receptor and has led to the hypothesis that the functional D3 receptor is located postsynaptically and exerts an inhibitory role on psychomotor function.