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

ABSTRACT

UNLABELLED Recent efforts have suggested that the ß-adrenergic receptor (ß-AR) system may be a novel and viable therapeutic target for pain reduction; however, most of the work to date has focused on the ß(2)-adrenergic receptor (AR). Here, we compared the antinociceptive effects of enantiomeric configurations of propranolol and bupranolol, two structurally similar nonselective ß-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 ß-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 ß-AR intrinsic agonist activity and displayed a full competitive antagonist profile at ß(1)/ß(2)/ß(3)-ARs, producing a unique blockade of ß(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 ß-AR intrinsic agonist activity and unique blockade of ß(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 ß-receptor antagonist, shows greater antinociceptive efficacy and a superior preclinical safety profile and it should be considered as a unique ß-adrenergic receptor compound to advance future clinical pain studies.