IUPHAR themed review: Opioid efficacy, bias, and selectivity

Area of Science:

• Pharmacology
• Neuroscience
• Medicinal Chemistry

Background:

• Opioid receptor agonists are used for pain but have significant side effects and abuse potential.
• Mu and kappa opioid receptors are primary targets, with mu-agonism causing constipation, dependence, and respiratory depression, while kappa-agonism causes dysphoria and sedation.
• The demand for safer analgesics drives research into novel opioid-based therapeutics.

Purpose of the Study:

• To review recent advancements in developing safer opioid analgesics.
• To discuss novel strategies including biased agonism, orthosteric site sub-pocket targeting, and Gα subtype selectivity.
• To evaluate the potential of kappa opioid receptors and new approaches for safer pain management.

Main Methods:

• Review of recent scientific literature on opioid receptor pharmacology and drug development.
• Analysis of structural and functional data related to opioid receptor bias.
• Exploration of emerging concepts like Gα subtype selectivity for targeted opioid therapy.

Main Results:

• Biased agonism at mu opioid receptors may not be the optimal strategy for developing safer analgesics.
• Kappa opioid receptors still hold promise for developing safer analgesics.
• Targeting sub-pockets within the orthosteric site offers a novel approach to fine-tune receptor activation.

Conclusions:

• Novel strategies beyond traditional biased agonism are needed for safer opioid analgesics.
• Kappa opioid receptor modulation and Gα subtype selectivity represent promising avenues for future research.
• A deeper understanding of opioid receptor structural dynamics is crucial for designing effective and safe pain medications.