title: Differences in the Antinociceptive Effects and Binding Properties of Propranolol and Bupranolol Enantiomers.
abstract: Recent efforts have suggested that the β-adrenergic receptor (β-AR) system may be a novel and viable therapeutic target for pain reduction; however, most of the work to date has focused on the β(2)-adrenergic receptor (AR). Here, we compared the antinociceptive effects of enantiomeric configurations of propranolol and bupranolol, two structurally similar nonselective β-blocking drugs, against mouse models of inflammatory and chronic pain. In addition, we calculated in silico docking and measured the binding properties of propranolol and bupranolol for all 3 β-ARs. Of the agents examined, S-bupranolol is superior in terms of its antinociceptive effect and exhibited fewer side effects than propranolol or its associated enantiomers. In contrast to propranolol, S-bupranolol exhibited negligible β-AR intrinsic agonist activity and displayed a full competitive antagonist profile at β(1)/β(2)/β(3)-ARs, producing a unique blockade of β(3)-ARs. We have shown that S-bupranolol is an effective antinociceptive agent in mice without negative side effects. The distinctive profile of S-bupranolol is most likely mediated by its negligible β-AR intrinsic agonist activity and unique blockade of β(3)-AR. These findings suggest that S-bupranolol instead of propranolol may represent a new and effective treatment for a variety of painful conditions.
  
  
  CONCLUSIONS
  The S enantiomer of bupranolol, a β-receptor antagonist, shows greater antinociceptive efficacy and a superior preclinical safety profile and it should be considered as a unique β-adrenergic receptor compound to advance future clinical pain studies.
authors.affiliation: Department of Psychology, McGill University, Montreal, Quebec, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Department of Psychology, University of Toronto Mississauga, Mississauga, Ontario, Canada. Electronic address: lj.martin@utoronto.ca.
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Department of Anesthesiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Marjo H
authors.initials: MH
authors.lastname: Piltonen
authors.affiliation: Center for Pain Research and Innovation, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Josee
authors.initials: J
authors.lastname: Gauthier
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Marino
authors.initials: M
authors.lastname: Convertino
authors.affiliation: Department of Psychology, McGill University, Montreal, Quebec, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Department of Psychology, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Erinn L
authors.initials: EL
authors.lastname: Acland
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
authors.affiliation: Department of Psychology, McGill University, Montreal, Quebec, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Department of Anesthesiology, McGill University, Montreal, Quebec, Canada; Center for Pain Research and Innovation, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
authors.affiliation: Center for Pain Research and Innovation, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: William
authors.initials: W
authors.lastname: Maixner
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002046:Bupranolol / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D059225:Nociception / Q000187:drug effects*; D010147:Pain Measurement; D011433:Propranolol / Q000737:chemistry / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D000319:Adrenergic beta-Antagonists; D000700:Analgesics; D011943:Receptors, Adrenergic, beta; D002046:Bupranolol; D011433:Propranolol
keywords: Pain; antinociception; bupranolol; propranolol; β-adrenergic receptors