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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...
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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
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Functional selectivity and dualsteric/bitopic GPCR targeting.

Ramona Schrage1, Evi Kostenis2

  • 1Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, Germany.

Current Opinion in Pharmacology
|December 28, 2016
PubMed
Summary
This summary is machine-generated.

Functional selectivity allows targeted engagement of G protein-coupled receptor pathways. Dualsteric/bitopic ligands show promise for developing diverse biased agonists with potential clinical benefits.

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Drug Discovery

Background:

  • G protein-coupled receptors (GPCRs) possess pleiotropic signaling capabilities.
  • Functional selectivity aims to target specific signaling pathways of GPCRs.
  • Biased agonists offer a strategy to achieve this selectivity.

Purpose of the Study:

  • To explore functional selectivity as a method for engaging specific GPCR signaling pathways.
  • To highlight the potential of dualsteric/bitopic ligands in generating functionally selective compounds.
  • To investigate the design principle of dualsteric/bitopic ligands for inducing signaling bias.

Main Methods:

  • Review of existing literature on functional selectivity and biased agonism.
  • Analysis of dualsteric/bitopic hybrid compounds as a class of functionally selective ligands.
  • Discussion of the binding topography and its role in disrupting receptor flexibility.

Main Results:

  • Signaling biased compounds at angiotensin II and μ opioid receptors have advanced to clinical trials.
  • Dualsteric/bitopic ligands are identified as a recent advancement in functionally selective agents.
  • The binding topography of dualsteric/bitopic compounds is well-suited for inducing signaling bias.

Conclusions:

  • Functional selectivity offers a novel approach to modulate GPCR signaling.
  • Dualsteric/bitopic design principles are highly promising for creating diverse biased agonists.
  • This approach holds potential for developing therapeutics with improved clinical outcomes.