title: Signalling profile differences: paliperidone versus risperidone.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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-HT2A ), human serotonin 2C receptor subtype and human histamine H1 receptors.
  
  
  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-HT2A -mediated recruitment of β-arrestin, 5-HT2A -mediated sensitization of ERK, and dopamine D2 -mediated sensitization of adenylyl cyclase signalling, both paliperidone and risperidone behaved as agonists.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: W P
authors.initials: WP
authors.lastname: Clarke
authors.forename: T A
authors.initials: TA
authors.lastname: Chavera
authors.forename: M
authors.initials: M
authors.lastname: Silva
authors.forename: L C
authors.initials: LC
authors.lastname: Sullivan
authors.forename: K A
authors.initials: KA
authors.lastname: Berg
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D019390:Arrestins / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017442:Histamine Agonists / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018967:Risperidone / Q000737:chemistry / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014162:Transfection; D000071557:beta-Arrestins
chemical_list: D014150:Antipsychotic Agents; D019390:Arrestins; C581293:DRD2 protein, human; D018491:Dopamine Agonists; D017442:Histamine Agonists; D007555:Isoxazoles; D011743:Pyrimidines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017448:Receptors, Dopamine D2; D011969:Receptors, Histamine H1; D017366:Serotonin Receptor Agonists; D000071557:beta-Arrestins; D048049:Extracellular Signal-Regulated MAP Kinases; D000262:Adenylyl Cyclases; D018967:Risperidone; D000068882:Paliperidone Palmitate
keywords: GPCR; antipsychotics; biased agonism; dopamine; functional selectivity; histamine; schizophrenia; serotonin