Heteromerization, Biased Agonism, and Allosteric Modulation of G Protein-Coupled Receptors in Addiction: Mechanistic Insights and Therapeutic Implications - PubMed
3 hours ago
- #GPCR mechanisms
- #addiction treatment
- #therapeutic selectivity
- GPCRs are central to psychoactive drug action in reward and stress circuits, but current treatments for addiction have limited success due to complex in vivo signaling contexts.
- The review highlights three key mechanisms for therapeutic selectivity: GPCR heteromerization, biased agonism, and allosteric modulation, focusing on dopaminergic, opioid, cannabinoid, and metabotropic glutamate systems.
- For heteromerization, evidence is graded from proximity-based findings to in vivo validation, emphasizing the need for robust functional confirmation.
- In μ-opioid receptor biased agonism, preclinical claims are critically reassessed, noting confounding factors like assay amplification and endpoint choice that limit clinical safety translation.
- Allosteric modulation, particularly with mGlu2/3 positive modulators, shows relapse-relevant promise but faces hurdles such as probe dependence and species differences.
- The translation of these mechanisms requires moving beyond single-receptor models, linking target engagement to circuit-level outcomes and meaningful clinical endpoints like relapse prevention.
- Future advances depend on integrating structural pharmacology with in vivo biomarkers, standardized trials, long-term safety evaluation, and equitable treatment access.