Differences in the Antinociceptive Effects and Binding Properties of Propranolol and Bupranolol Enantiomers

Loren J. Martin, Marjo H. Piltonen, Josee Gauthier, Marino Convertino, Erinn L. Acland, Nikolay Dokholyan, Jeffrey S. Mogil, Luda Diatchenko, William Maixner

Research output: Contribution to journalArticle

12 Scopus citations

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 β2-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 β123-ARs, producing a unique blockade of β3-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 β3-AR. These findings suggest that S-bupranolol instead of propranolol may represent a new and effective treatment for a variety of painful conditions. Perspective 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.

Original languageEnglish (US)
Pages (from-to)1321-1333
Number of pages13
JournalJournal of Pain
Volume16
Issue number12
DOIs
StatePublished - Jan 1 2015

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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    Martin, L. J., Piltonen, M. H., Gauthier, J., Convertino, M., Acland, E. L., Dokholyan, N., Mogil, J. S., Diatchenko, L., & Maixner, W. (2015). Differences in the Antinociceptive Effects and Binding Properties of Propranolol and Bupranolol Enantiomers. Journal of Pain, 16(12), 1321-1333. https://doi.org/10.1016/j.jpain.2015.09.004