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Related Concept Videos

Agonism and Antagonism: Quantification01:14

Agonism and Antagonism: Quantification

When drugs are administered, they can elicit either an agonist or antagonist effect on the body. Agonism occurs when a drug activates a specific receptor, triggering a biological response. On the other hand, antagonism happens when a drug binds to the same receptors but blocks their activation, thereby preventing a biological response.
To quantify these effects, researchers use a dose-response curve, which provides valuable information about the potency and efficacy of a drug. Potency refers to...
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...
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...
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...
Drug-Receptor Interaction: Agonist01:25

Drug-Receptor Interaction: Agonist

Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous ligand's action.
Quantitative Aspects of Drug-Receptor Interaction01:30

Quantitative Aspects of Drug-Receptor Interaction

The receptor occupancy theory connects a drug's response to the number of occupied receptors. With higher drug concentrations, more receptors are occupied, leading to increased responses. The formation of drug-receptor complexes involves association and dissociation rates, which reach equilibrium when the forward and backward reactions are equal. The equilibrium association constant (Ka) and its inverse, the equilibrium dissociation constant (Kd), indicate drug affinity. Higher Ka and lower Kd...

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Quantifying Agonist Activity at G Protein-coupled Receptors
11:45

Quantifying Agonist Activity at G Protein-coupled Receptors

Published on: December 26, 2011

A simple method for quantifying functional selectivity and agonist bias.

Terry Kenakin1, Christian Watson, Vanessa Muniz-Medina

  • 1Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7365, USA. Kenakin@email.unc.edu

ACS Chemical Neuroscience
|August 4, 2012
PubMed
Summary
This summary is machine-generated.

New methods quantify biased agonism for seven-transmembrane (7TM) receptors, addressing cell-type variability in drug discovery. This approach aids in optimizing drug candidates by evaluating receptor activation and signaling pathway bias.

Keywords:
Biased agonismdrug discoveryfunctional selectivityreceptor methodsreceptor theorystimulus bias

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Area of Science:

  • Pharmacology and Drug Discovery
  • Molecular and Cellular Biology
  • Biochemistry

Background:

  • Seven-transmembrane (7TM) receptors exhibit functional selectivity, where agonists activate specific signaling pathways, leading to biased responses.
  • Cell type-dependent variability in agonist responses complicates drug profiling and medicinal chemistry efforts for targeted therapies.
  • Understanding and quantifying agonist bias is crucial for developing effective therapeutics that leverage specific receptor signaling.

Purpose of the Study:

  • To develop a quantitative scale based on the Black and Leff operational model to describe 7TM receptor agonism.
  • To introduce a 'transduction coefficient' (log(τ/K(A))) for statistically evaluating selective agonist effects and guiding drug discovery.
  • To address the challenge of cell type dependence in agonist profiling for therapeutic applications.

Main Methods:

  • Utilized the Black and Leff operational model to define a scale incorporating receptor affinity (K(A) (-1)) and signaling pathway efficacy (τ).
  • Introduced and applied a 'transduction coefficient' (log(τ/K(A))) to quantify agonist bias.
  • Quantified the bias of four chemokines for CCR5-mediated inositol phosphate production versus internalization.

Main Results:

  • Developed a statistically robust scale for evaluating 7TM receptor agonism and functional selectivity.
  • Demonstrated the practical application of the 'transduction coefficient' in quantifying chemokine bias for CCR5.
  • Confirmed the method's independence from receptor density and discussed statistical confidence estimates.

Conclusions:

  • The proposed scale and transduction coefficient provide a valuable tool for assessing agonist bias in a manner that can inform structure-activity relationship studies.
  • This quantitative approach aids in the selection and optimization of drug candidates by characterizing their specific signaling profiles.
  • The method offers a statistically sound framework for understanding and exploiting functional selectivity in drug development.