# Indole Alkaloids as Biased Opioid Receptor Modulators

## TL;DR

Indole alkaloids like ibogaine and mitragynine may offer safer pain relief by activating opioid receptors without causing severe side effects.

## Contribution

The study reveals that indole alkaloids act as biased opioid receptor modulators, potentially reducing adverse effects like respiratory depression.

## Key findings

- Indole alkaloids act as biased agonists on μ-opioid receptors with reduced β-arrestin recruitment.
- The indole structure accommodates a different spatial orientation in key receptor regions, explaining biased activation.
- Biased activation limits adverse effects, suggesting potential for safer opioid drugs.

## Abstract

Background: Opioid receptors are a commonly used target for treatment of pain conditions. Most opioids used in therapy are linked to adverse effects such as tolerance, dependence, and respiratory depression. Indole alkaloids acting on opioid receptors may provide a novel molecular mechanism to confer analgesic effects. Results: Indole alkaloids such as ibogaine and mitragynine act on μ-opioid receptors as biased full or partial agonists that do not, or much less strongly, recruit β-arrestin compared to non-biased agonists. The recruitment of β-arrestin has been linked to adverse effects, most notably substantial respiratory depression. The molecular mechanism of biased activation has been proposed to be associated with accommodation of the indole structure that leads to a different spatial orientation of amino acid residues in transmembrane regions 2 and 3 of the μ-opioid receptor as well as extracellular helix 8. Conclusions: Naturally occurring indole alkaloids show biased G-protein coupled activation of opioid receptors with limited recruitment of β-arrestin, thus limiting commonly observed adverse effects. Indole alkaloids may present a feasible structure to develop new biased opioid modulators with an improved risk-to-benefit ratio.