Limitations to dopamine D2 ligands for antipsychotic efficacy.
The D2 receptor has often been examined as the target for antipsychotic drugs due to its distribution in critical areas of the brain involved in movement and reward. Beta-arrestin biased drugs such as UNC9994 function as antagonists through G-protein signaling and partial agonists through beta-arrestin signaling, which has been shown to decrease psychotic properties while minimizing unwanted side effects. Of the five dopamine receptors, D2 closely mirrors D3 and D4. Therefore, it has been proposed that these novel therapeutics may be having an effect on the dopamine D3 and D4 receptors. Using BRET assays with HEK293 cell lines, aripiprazole and its congener UNC9994 have been tested on the dopamine D2-D4 receptors, and their effects were recorded as dose-response curves. By comparing the effect of the drugs to the effect of the natural ligand dopamine, it has been discovered that these agents do have an effect at the D3 and D4 receptors. Due to the role of non-D2 dopamine receptors in contributing to many of the symptoms of schizophrenia, novel therapeutic agents remain to be developed that could have the receptor specificity needed to attenuate psychotic phenotypes while minimizing unwanted side effects.