Biased agonism: the quest for the analgesic holy grail

Abstract

Opioids alleviate pain, but adverse effects severely limit their usefulness. To solve this problem, biased ligands favoring 1 signaling pathway downstream of the μ-opioid receptor over another are being developed. In the target article, the authors synthesize compounds that preferentially activate G-protein or β-arrestin signaling. They find that increased bias towards G-protein signaling produces better antinociception with minimal side effects in mice models. G-protein-biased opioids may provide a safer treatment strategy.

Keywords: Bias; Functional selectivity; Opioid; Signaling.

Figure 1.

G-protein–biased compounds produce antinociception with reduced side effects. Fentanyl is a clinically used opioid analgesic that preferentially recruits β-arrestin downstream of the μ-opioid receptor (left). Consequently, fentanyl produces significant respiratory depression. In the target article, Schmid et al. synthesize SR-17018, an opioid that preferentially engages G-protein signaling (right). The authors demonstrate that SR-17018 produces antinociception with minimal respiratory depression relative to fentanyl.