title: Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT 2A receptors: functional receptor-binding and in vivo electrophysiological studies.
abstract: BACKGROUND
  Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics. Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors.
  
  
  METHODS
  This study examined aripiprazole's interactions with 5-HT systems in vitro and in vivo to further clarify its pharmacologic properties.
  
  
  RESULTS
  Aripiprazole produced increases in [(35)S]GTPgammaS binding to rat hippocampal membranes. Its potency (pEC(50) = 7.2) was similar to that of ziprasidone (7.1) and greater than that of 5-HT (6.7) and buspirone (6.4), a 5-HT(1A)-receptor partial agonist, whereas its intrinsic activity was similar to that of ziprasidone and buspirone. The stimulatory effect of aripiprazole was blocked by WAY-100635, a 5-HT(1A)-receptor antagonist. In in vivo electrophysiology studies, aripiprazole produced a dose-related reduction in the firing rate of 5-HT-containing dorsal raphe neurons in rats, which was both prevented and reversed by WAY-100635 administration. Aripiprazole showed a high affinity for human 5-HT(1A) receptors (K (i) = 4.2 nM) using parietal cortex membrane preparations. In membranes from cells expressing human recombinant receptors, aripiprazole bound with high affinity to 5-HT(2A) receptors (K (i) = 3.4 nM), moderate affinity to 5-HT(2C) (K (i) = 15 nM) and 5-HT(7) (K (i) = 39 nM) receptors, and low affinity to 5-HT(6) receptors (K (i) = 214 nM) and 5-HT transporter (K (i) = 98 nM). In addition, aripiprazole potently blocked 5-HT(2A)-receptor-mediated increases in intracellular Ca(2+) levels in a rat pituitary cell line (IC(50) = 11 nM).
  
  
  CONCLUSIONS
  These results support a partial agonist activity for aripiprazole at 5-HT(1A) receptors in vitro and in vivo, and suggest important interactions with other 5-HT-receptor subtypes. This receptor activity profile may contribute to the antipsychotic activity of aripiprazole in humans.
authors.affiliation: Neuroscience Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. arlene.stark@bms.com
authors.forename: Arlene D
authors.initials: AD
authors.lastname: Stark
authors.forename: Shaun
authors.initials: S
authors.lastname: Jordan
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Allers
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bertekap
authors.forename: Ruoyan
authors.initials: R
authors.lastname: Chen
authors.forename: Tanaz
authors.initials: T
authors.lastname: Mistry Kannan
authors.forename: Thaddeus F
authors.initials: TF
authors.lastname: Molski
authors.forename: Frank D
authors.initials: FD
authors.lastname: Yocca
authors.forename: Trevor
authors.initials: T
authors.lastname: Sharp
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burris
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D011869:Radioligand Assay; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D044402:Receptor, Serotonin, 5-HT2A; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D000068180:Aripiprazole; D002118:Calcium