title: Molecular and behavioral pharmacology of two novel orally-active 5HT2 modulators: potential utility as antipsychotic medications.
abstract: BACKGROUND
  Desired serotonin 5HT2 receptor pharmacology for treatment of psychoses is 5HT2A antagonism and/or 5HT2C agonism. No selective 5HT2A antagonist has been approved for psychosis and the only approved 5HT2C agonist (for obesity) also activates 5HT2A and 5HT2B receptors, which can lead to clinical complications. Studies herein tested the hypothesis that a dual-function 5HT2A antagonist/5HT2C agonist that does not activate 5HT2B receptors would be suitable for development as an antipsychotic drug, without liability for weight gain.
  
  
  METHODS
  The novel compounds (+)- and (-)-trans-4-(4'-chlorophenyl)-N,N-dimethyl-2-aminotetralin (p-Cl-PAT) were synthesized, characterized in vitro for affinity and functional activity at human 5HT2 receptors, and administered by intraperitoneal (i.p.) and oral (gavage) routes to mice in behavioral paradigms that assessed antipsychotic efficacy and effects on feeding behavior.
  
  
  RESULTS
  (+)- and (-)-p-Cl-PAT activated 5HT2C receptors, with (+)-p-Cl-PAT being 12-times more potent, consistent with its higher affinity across 5HT2 receptors. Neither p-Cl-PAT enantiomer activated 5HT2A or 5HT2B receptors at concentrations up to 300-times greater than their respective affinity (Ki), and (+)-p-Cl-PAT was shown to be a 5HT2A competitive antagonist. When administered i.p. or orally, (+)- and (-)-p-Cl-PAT attenuated the head-twitch response (HTR) in mice elicited by the 5HT2 agonist (-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and reduced intake of a highly palatable food in non-food-deprived mice, with (+)-p-Cl-PAT being more potent across behavioral assays.
  
  
  CONCLUSIONS
  The novel in vitro pharmacology of (+)-p-Cl-PAT (5HT2A antagonism/5HT2C agonism without activation of 5HT2B) translated in vivo to an orally-active drug candidate with preclinical efficacy to treat psychoses without liability for weight gain.
authors.affiliation: Department of Psychiatry, College of Medicine, University of Florida, Gainesville, FL, USA. drakem@ufl.edu
authors.forename: Drake
authors.initials: D
authors.lastname: Morgan
authors.forename: Krishnakanth
authors.initials: K
authors.lastname: Kondabolu
authors.forename: Allison
authors.initials: A
authors.lastname: Kuipers
authors.forename: Rajeev
authors.initials: R
authors.lastname: Sakhuja
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Robertson
authors.forename: Neil E
authors.initials: NE
authors.lastname: Rowland
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Booth
mesh_terms: D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000493:pharmacokinetics; D005518:Food Preferences / Q000187:drug effects / Q000502:physiology; D006016:Glycolates / Q000494:pharmacology; D019416:Head Movements / Q000187:drug effects; D006801:Humans; D007650:Ketanserin / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D000662:Amphetamines; D014150:Antipsychotic Agents; D004873:Ergolines; D006016:Glycolates; C528865:N-(2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxothiazolidin-3-yl-(4-chlorophenoxy))acetamide; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014316:Tritium; D007650:Ketanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; C031649:mesulergine