Opioids are a class of drugs derived from natural substances found in the opium poppy plant and are primarily prescribed for the treatment of acute and chronic pain conditions. Despite their effectiveness, these medications come with significant risks and side effects and are often abused, leading to addiction and deaths due to overdose. Therefore, there is a significant need to develop novel analgesics with reduced risk and side effects. Opioids achieve their function through interacting with the opioid family of g protein-coupled receptors (GPCRs) which includes the mu, delta, kappa, and nociceptive receptors (MOR, DOR, KOR and NOPR). These receptors are activated by opioids or endogenous peptides binding to their highly conserved orthosteric sites and undergo a conformational change to mediate downstream signalling via the Gi/o or arrestin pathways.
In recent years, allosteric modulation of GPCRs has become a major area of interest for drug discovery. This modulation involves an allosteric ligand binding to a distinct site, separate from the orthosteric site, and influencing the affinity and efficacy of the orthosteric ligand. Opioid allosteric modulators present a promising avenue as an alternative to orthosteric ligands. They have the potential to achieve comparable analgesia by enhancing the body's response to endogenous peptide hormones while minimising adverse effects. However, the molecular understanding of allosteric modulation of the opioid receptors remains largely elusive.
Here we have used a combination of medicinal chemistry, molecular pharmacology, and cryo-electron microscopy (Cryo-EM) to investigate the molecular mechanisms of allosteric modulation of the delta opioid receptor (DOR). These results open the way for the development of a novel class of therapeutics that target opioid receptors.