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Functional selectivity and classical concepts of quantitative pharmacology
Jonathan D Urban1, William P Clarke, Mark von Zastrow
1Curriculum in Toxicology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7160, USA.
Summary
Functional selectivity, or biased agonism, challenges traditional pharmacology by showing ligands can activate specific pathways of a single receptor. This discovery offers new avenues for optimizing drug discovery and therapeutic actions.
Area of Science:
- Pharmacology
- Biochemistry
- Drug Discovery
Background:
- The traditional concept of intrinsic efficacy in pharmacology is being challenged by new data.
- Ligands can differentially activate signaling pathways via a single G protein-coupled receptor (GPCR).
- This phenomenon is known as functional selectivity, agonist-directed trafficking, or biased agonism.
Purpose of the Study:
- To explore the concept of functional selectivity and its implications in pharmacology.
- To present data illustrating functional selectivity across various receptor systems.
- To discuss the mechanisms and potential impact of functional selectivity on drug discovery.
Main Methods:
- Review of recent data on ligand-receptor interactions.
- Examination of signaling pathways mediated by GPCRs.
- Analysis of data from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems.
Main Results:
- Functionally selective ligands can act as both agonists and antagonists at different functions of the same receptor.
- Examples are provided from multiple neurotransmitter and hormone receptor systems.
- Mechanisms include ligand-induced conformational changes, G protein diversity, scaffolding, and receptor oligomers.
Conclusions:
- Functional selectivity is an apparently ubiquitous phenomenon with significant implications for drug discovery.
- Novel ligands can be designed to selectively activate specific receptor functions, optimizing therapeutic effects.
- Classic concepts in quantitative pharmacology may need revision to incorporate these findings.
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