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

J Pain. 2015 Dec;16(12):1321-1333. doi: 10.1016/j.jpain.2015.09.004. Epub 2015 Oct 9.

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.

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.

Keywords: Pain; antinociception; bupranolol; propranolol; β-adrenergic receptors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / chemistry
  • Adrenergic beta-Antagonists / pharmacology*
  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Animals
  • Bupranolol / chemistry
  • Bupranolol / pharmacology*
  • Disease Models, Animal
  • Female
  • Male
  • Mice
  • Nociception / drug effects*
  • Pain Measurement
  • Propranolol / chemistry
  • Propranolol / pharmacology*
  • Receptors, Adrenergic, beta / chemistry
  • Receptors, Adrenergic, beta / metabolism*
  • Stereoisomerism

Substances

  • Adrenergic beta-Antagonists
  • Analgesics
  • Receptors, Adrenergic, beta
  • Bupranolol
  • Propranolol