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Related Concept Videos

Dose-Response Relationship: Selectivity and Specificity01:25

Dose-Response Relationship: Selectivity and Specificity

Drugs exert their therapeutic effects by interacting with receptors, enzymes, or ion channels that are present throughout the human body. The strength and duration of the interaction between a drug and its target receptor are characterized by the selectivity and specificity of the drug. Selectivity refers to a drug's strong preference for its intended target over other targets. For instance, isoprenaline, a non-selective β-adrenergic agonist, interacts with both β1- and β2-adrenergic receptors...
The Two-State Receptor Model01:29

The Two-State Receptor Model

The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with one...
Spare Receptors01:30

Spare Receptors

Some receptors remain unoccupied even when an agonist produces a maximal response. Such empty ones are called spare receptors. In presence of spare receptors the maximum effect of an agonist drug is achieved with fewer than 100% of the receptors being occupied. To determine the presence of spare receptors, scientists often compare the concentration of the drug needed to produce 50% of the maximum effect (EC50) with the concentration of the drug needed to occupy 50% of the receptors (Kd). If the...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
Drug-Receptor Interactions01:29

Drug-Receptor Interactions

Drug-receptor interaction describes the binding of receptors by drugs, but not all drug-receptor interactions result in activation and tissue response. For instance, the binding of agonists activates the receptor to generate a cellular reaction, while antagonists bind to receptors without causing their activation.
Several parameters, such as the drug's affinity for its receptor and its efficacy, which is its ability to activate the receptor, determine the drug's effect on the tissue.
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Drug-Receptor Bonds

Drug-receptor bonds are formed through various chemical forces when drugs interact with target cells. Covalent bonds, strong and irreversible, are exemplified by DNA-alkylating anticancer agents that inhibit cell division. However, such irreversible drug binding lacks selectivity and can modify the DNA of the surrounding healthy cells. Covalent binding often contributes to tissue toxicity, as seen with chloroform and paracetamol metabolites binding to the liver, causing hepatotoxicity.
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BRET-based G Protein Biosensors for Measuring G Protein-Coupled Receptor Activity in Live Cells
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Functional selectivity and biased receptor signaling.

Terry Kenakin1

  • 1Platform Technology Sciences, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA. terry.p.kenakin@gsk.com

The Journal of Pharmacology and Experimental Therapeutics
|October 30, 2010
PubMed
Summary
This summary is machine-generated.

Biased ligands can stabilize unique seven-transmembrane receptor conformations, leading to cell-specific signaling. This challenges traditional drug classification and requires targeted assays for accurate detection and optimization.

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Area of Science:

  • Pharmacology
  • Biochemistry
  • Drug Discovery

Background:

  • Seven-transmembrane receptors (7TMRs) exhibit pleiotropic signaling capabilities.
  • Ligands can stabilize distinct receptor conformations, leading to biased signaling pathways.
  • Traditional assays struggle with detecting functional selectivity and biased agonism.

Purpose of the Study:

  • To address the challenges posed by functional selectivity and biased ligands in drug discovery.
  • To highlight the need for targeted assays to detect and quantify cell-specific agonism.
  • To discuss the implications for pharmacologic nomenclature and drug optimization.

Main Methods:

  • Review of current literature on seven-transmembrane receptor signaling.
  • Analysis of concepts including functional selectivity, biased agonism, and pluridimensional efficacy.
  • Discussion of assay limitations and future directions in drug characterization.

Main Results:

  • Ligands can stabilize unique 7TMR conformations, resulting in selective pathway activation.
  • "Biased" ligands demonstrate cell-specific agonism, defying "one size fits all" assay approaches.
  • Pluridimensional efficacy challenges conventional agonist/antagonist classifications.

Conclusions:

  • The discovery of biased ligands necessitates a paradigm shift in drug discovery and characterization.
  • Targeted assays are crucial for detecting and quantifying the nuanced pharmacological profiles of biased ligands.
  • Understanding pluridimensional efficacy is vital for accurate drug nomenclature and correlating drug properties with clinical outcomes.