| Summary: | Dopamine D<sub>2</sub> receptors (D<sub>2</sub>R) are known to form transient homodimer complexes, of which the increased formation has already been associated with development of schizophrenia. Pharmacological targeting and modulation of the equilibrium of these receptor homodimers might lead to a better understanding of the critical role played by these complexes in physiological and pathological conditions. Whereas agonist addition has shown to prolong the D<sub>2</sub>R dimer lifetime and increase the level of dimer formation, the possible influence of D<sub>2</sub>R antagonists on dimerization has remained rather unexplored. Here, using a live-cell reporter assay based on the functional complementation of a split Nanoluciferase, a panel of six D<sub>2</sub>R antagonists were screened for their ability to modulate the level of D<sub>2L</sub>R dimer formation. Incubation with the D<sub>2</sub>R antagonist spiperone decreased the level of D<sub>2L</sub>R dimer formation significantly by 40–60% in real-time and after long-term (≥16 h) incubations. The fact that dimer formation of the well-studied A<sub>2a</sub>–D<sub>2L</sub>R dimer was not altered following incubation with spiperone supports the specificity of this observation. Other D<sub>2</sub>R antagonists, such as clozapine, risperidone, and droperidol did not significantly evoke this dissociation event. Furthermore, molecular modeling reveals that spiperone presents specific Tyr199<sup>5.48</sup> and Phe390<sup>6.52</sup> conformations, compared to clozapine, which may determine D<sub>2</sub>R homodimerization.
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