Exploring the kinetic selectivity of antipsychotics for dopamine D2 and 5-HT2A receptors: implications for the prevalence of EPS and receptor occupancy

Certain atypical antipsychotic drugs (APDs) used in the treatment of schizophrenia have been hypothesized to show reduced extrapyramidal side effects (EPS), due to their ability to promote nigrostriatal dopamine release through 5-HT2A receptor (5-HT2AR) blockade. The strength of this hypothesis is currently limited to a consideration of the relative receptor affinities of APDs for the 5-HT2AR and dopamine D2 receptor (D2R). Here we measure the 5-HT2AR kinetic binding properties of a series of typical and atypical APDs in a novel time-resolved fluorescence resonance energy transfer assay and correlate these properties with their observed EPS at therapeutic doses. For compounds with negligible affinity for 5-HT2AR, EPS is robustly predicted by a D2R specific rebinding model that integrates D2R association and dissociation rates to calculate the net rate of reversal of receptor blockade (kr). However, we show that for compounds with significant affinity for the 5-HT2AR, such as sertindole, higher relative 5-HT2A occupancy over time is an indicator for a reduced propensity to cause EPS. This study suggests that there is room for the development of novel kinetically optimised antipsychotic agents that modulate both serotonergic and dopamine function in a manner beneficial in the treatment of this chronic and debilitating disease.