title: Molecular interactions between general anesthetics and the 5HT2B receptor.
abstract: BACKGROUND
  Serotonin modulates many processes through a family of seven serotonin receptors. However, no studies have screened for interactions between general anesthetics currently in clinical use and serotonergic G-protein-coupled receptors (GPCRs). Given that both intravenous and inhalational anesthetics have been shown to target other classes of GPCRs, we hypothesized that general anesthetics might interact directly with some serotonin receptors and thus modify their function.
  
  
  METHODS
  Radioligand binding assays were performed to screen serotonin receptors for interactions with propofol and isoflurane as well as for affinity determinations. Docking calculations using the crystal structure of 5-HT2B were performed to computationally confirm the binding assay results and locate anesthetic binding sites.
  
  
  RESULTS
  The 5-HT2B class of receptors interacted significantly with both propofol and isoflurane in the primary screen. The affinities for isoflurane and propofol were determined to be 7.78 and .95 μM, respectively, which were at or below the clinical concentrations for both anesthetics. The estimated free energy derived from docking calculations for propofol (-6.70 kcal/mol) and isoflurane (-5.10 kcal/mol) correlated with affinities from the binding assay. The anesthetics were predicted to dock at a pharmacologically relevant binding site of 5HT2B.
  
  
  CONCLUSIONS
  The molecular interactions between propofol and isoflurane with the 5-HT2B class of receptors were discovered and characterized. This finding implicates the serotonergic GPCRs as potential anesthetic targets.
authors.affiliation: a Department of Anesthesiology and Critical Care , Perelman School of Medicine, University of Pennsylvania , 336 John Morgan Building, 3620 Hamilton Walk, Philadelphia , PA 19104 , USA.
authors.forename: Felipe
authors.initials: F
authors.lastname: Matsunaga
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: Jeffery G
authors.initials: JG
authors.lastname: Saven
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Renyu
authors.initials: R
authors.lastname: Liu
mesh_terms: D018681:Anesthetics, General / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D006801:Humans; D006860:Hydrogen Bonding; D007530:Isoflurane / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D015742:Propofol / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011869:Radioligand Assay; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry* / Q000378:metabolism; D012694:Serine / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055672:Static Electricity; D013912:Threonine / Q000737:chemistry / Q000378:metabolism
chemical_list: D018681:Anesthetics, General; D044403:Receptor, Serotonin, 5-HT2B; D013912:Threonine; D012694:Serine; D007530:Isoflurane; D015742:Propofol
keywords: anesthetics; isoflurane; propofol; serotonin receptor