5 Conolidine is a rare C5-nor stemmadenine (Fig. Pharmacologists have only recently been able to confirm its medicinal and pharmacological properties thanks to its first asymmetric total synthesis. Among such natural analgesic molecules, conolidine, found in the bark of the tropical flowering shrub Tabernaemontana divaricata, also called pinwheel flower or crepe jasmine, has long been used in traditional Chinese, Ayurvedic and Thai medicines to treat fever and pain 4 (Fig.
Plants have been historically a source of analgesic alkaloids, although their pharmacological characterization is often limited. Nevertheless, the improved therapeutic ratio of such molecules was recently proposed to stem from their low intrinsic efficacy rather than their biased profile, 3 which further supports the importance of considering alternate strategies to modulate the opioid system. Several ligands were discovered through these efforts, including the μ-opioid receptor (MOR) agonists PZM21 and TRV130 (Oliceridine, recently approved by the FDA), which show little β-arrestin recruitment or receptor internalization in in vitro models.
These findings fueled extensive efforts over the last years to find so-called “G protein-biased ligands”, i.e., agonists of opioid receptors that preferentially trigger G protein activation over arrestin recruitment, with the hope to improve pain management by fine-tuning opioid receptor-mediated signal transduction. Indeed, reports from β-arrestin-2 knockout mouse models proposed that side effects observed with opioids such as morphine were mainly linked to β-arrestin-dependent intracellular events. Biased ligands, able to preferentially induce one signaling pathway over another, were regarded as a potential solution to this concern. There is an urgent need to find new means to modulate the opioid system, using drugs with alternative mechanisms of action and, crucially, improved safety profiles.
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