title: Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist but not antagonist binding to 5-HT2c receptors after chronic treatment.
abstract: BACKGROUND
  Sertindole is a novel antipsychotic drug with high affinity for dopamine D2, alpha-1-adrenoceptors and serotonin 5-HT2A and 5-HT2c receptors. The 5-HT2c receptor component of sertindole may be clinically relevant as this receptor subtype is implicated in regulation of anxiety, cognition/memory and brain plasticity.
  
  
  OBJECTIVE
  To characterise the interaction of sertindole with the 5-HT2C receptor using rat choroid plexus as a physiological receptor source.
  
  
  RESULTS
  Sertindole had nanomolar affinity for the 5-HT2c receptor in vitro. Sertindole antagonised 5-HT-stimulated phosphoinositide (PI) hydrolysis and, like clozapine, also inhibited basal PI hydrolysis suggesting that sertindole is a 5-HT2C receptor inverse agonist. The effect of repeated sertindole dosing on 5-HT2C receptors was studied in rats treated for 21 days with sertindole (20, 300 and 1250 microg/kg/day). Clozapine (25 mg/kg/day) was used as a comparison drug. 5-HT2C receptor binding in the choroid plexus was measured with antagonist and agonist ligands ([3H]mesulergine and [125I]DOI) using quantitative autoradiography 8 days after withdrawal. Clozapine decreased 5-HT2C receptor antagonist and agonist binding sites equally by 36% and 32%, respectively. Sertindole did not induce significant changes in the total number of 5-HT2C receptors, but the highest dose of sertindole lowered the affinity of [3H]mesulergine for 5-HT2C receptors. This was most likely due to residual sertindole levels in the brain which was supported by direct concentration measurements. In contrast, sertindole induced a highly significant and dose-related decrease in 5-HT2C agonist binding (up to 77%). Neither drug affected striatal D2 receptor binding.
  
  
  CONCLUSIONS
  Sertindole, like clozapine, was found to be a serotonin 5-HT2C receptor inverse agonist. The preferential downregulation of 5-HT2C receptor agonist (G-protein-coupled) sites by chronic administration seemed to differentiate sertindole from clozapine at these dose regimens. The 5-HT2c receptor downregulation during repeated dosing may contribute to therapeutic efficacy and/or side effects of sertindole treatment.
authors.affiliation: Department of Psychiatry and Turku PET Center, Turku University Central Hospital, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Hietala
authors.forename: M
authors.initials: M
authors.lastname: Kuonnamäki
authors.forename: E P
authors.initials: EP
authors.lastname: Pälvimäki
authors.forename: A
authors.initials: A
authors.lastname: Laakso
authors.forename: H
authors.initials: H
authors.lastname: Majasuo
authors.forename: E
authors.initials: E
authors.lastname: Syvälahti
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D007093:Imidazoles; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C066304:sertindole