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Concrete examples of biased agonism that have clearly improved therapeutic outcomes include the development of -arrestinbiased angiotensin II receptor ligands (which showed reduced hypertension-related adverse effects in preclinical models) and carfentanil-class opioid analogs designed to preferentially engage G-protein over arrestin pathways, thereby reducing respiratory depression ( 3.2 From single-target optimization to rational polypharmacology Another major shift influencing the relevance of underexplored peptide systems is the growing acceptance of rational polypharmacology

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