Signalling profile differences: Paliperidone versus risperidone

Background and Purpose Paliperidone is an active metabolite of the second-generation atypical antipsychotic, risperidone recently approved for the treatment of schizophrenia and schizoaffective disorder. Because paliperidone differs from risperidone by only a single hydroxyl group, questions have been raised as to whether there are significant differences in the effects elicited between these two drugs. Experimental Approach We compared the relative efficacies of paliperidone versus risperidone to regulate several cellular signalling pathways coupled to four selected GPCR targets that are important for either therapeutic or adverse effects: human dopamine D₂, human serotonin 2A receptor subtype (5-HT_2A), human serotonin 2C receptor subtype and human histamine H₁ receptors. Key Results Whereas the relative efficacies of paliperidone and risperidone were the same for some responses, significant differences were found for several receptor-signalling systems, with paliperidone having greater or less relative efficacy than risperidone depending upon the receptor-response pair. Interestingly, for 5-HT_2A-mediated recruitment of β-arrestin, 5-HT _2A-mediated sensitization of ERK, and dopamine D₂-mediated sensitization of adenylyl cyclase signalling, both paliperidone and risperidone behaved as agonists. Conclusions and Implications These results suggest that the single hydroxyl group of paliperidone promotes receptor conformations that can differ from those of risperidone leading to differences in the spectrum of regulation of cellular signal transduction cascades. Such differences in signalling at the cellular level could lead to differences between paliperidone and risperidone in therapeutic efficacy or in the generation of adverse effects.