title: Novel molecular targets of dezocine and their clinical implications.
abstract: BACKGROUND
  Although dezocine is a partial μ-opioid receptor agonist, it is not a controlled substance. Thus, the characterization of the molecular targets of dezocine is critical for scientific and clinical implications. The goal of this study is to characterize molecular targets for dezocine and determine their implications.
  
  
  METHODS
  A binding screen for dezocine was performed on 44 available receptors and transporter proteins. Functional assays for the novel targets were performed along with computation calculations to locate the binding site. A G protein activation study was performed for the human κ opioid receptor to determine whether dezocine is a κ-antagonist. Data are presented as mean ± standard error.
  
  
  RESULTS
  The affinities for dezocine were 3.7 ± 0.7 nM for the μ receptor, 527 ± 70 nM for the δ-receptor, and 31.9 ± 1.9 nM for the κ-receptor. Dezocine failed to induce G protein activation with κ-opioid receptor and concentration dependently inhibited κ-agonist (salvinorin A and nalbuphine)-induced receptor activation, indicating that dezocine is a κ-antagonist. Two novel molecular targets (norepinephrine transporter and serotonin transporter) were identified. Dezocine concentration-dependently inhibited norepinephrine and serotonin reuptake in vitro. The half maximal inhibitory concentrations (expressed as pIC50) were 5.68 ± 0.11 for norepinephrine transporter and 5.86 ± 0.17 for serotonin transporter. Dezocine occupied the binding site for known norepinephrine transporter and serotonin transporter inhibitors.
  
  
  CONCLUSIONS
  The unique molecular pharmacological profile of dezocine as a partial μ-receptor agonist, a κ-receptor antagonist, and a norepinephrine and serotonin reuptake inhibitor (via norepinephrine transporter and serotonin transporter) was revealed. These discoveries reveal potentially important novel clinical implications and drug interactions of dezocine.
authors.affiliation: From the Department of Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (R.L. and J.X.); National Institute of Mental Health Psychoactive Drug Screening Program and Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina (X-P.H. and B.L.R.); and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland (A.Y.).
authors.forename: Renyu
authors.initials: R
authors.lastname: Liu
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: Alexei
authors.initials: A
authors.lastname: Yeliseev
authors.forename: Jin
authors.initials: J
authors.lastname: Xi
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009292:Narcotic Antagonists; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009292:Narcotic Antagonists; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D050486:Serotonin Plasma Membrane Transport Proteins; D013764:Tetrahydronaphthalenes; C010827:dezocine