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Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity. | LitMetric

Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity.

Int J Neuropsychopharmacol

Department of Pharmacology, University of Texas Health, San Antonio, Texas.

Published: October 2018

AI Article Synopsis

  • - The concepts of constitutive receptor activity/inverse agonism and functional selectivity/biased agonism are changing how we understand drug interactions with receptors, revealing that receptors can be active even without a ligand.
  • - Inverse agonists can decrease this constitutive activity of receptors, acting oppositely to traditional agonists, while functional selectivity allows a drug to exhibit different effects (agonist, antagonist, inverse agonist) at the same receptor depending on the specific response being measured.
  • - These findings are significant for drug development and medical applications, as they show that drugs can have complex behaviors and selectivity that go beyond the established theories of receptor activity.

Article Abstract

Constitutive receptor activity/inverse agonism and functional selectivity/biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional receptor theory postulated that receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy. We now know that receptors can be active without an activating ligand and thus display "constitutive" activity. As a result, a new class of ligand was discovered that can reduce the constitutive activity of a receptor. These ligands produce the opposite effect of an agonist and are called inverse agonists. The second topic discussed is functional selectivity, also commonly referred to as biased agonism. Traditional receptor theory also posited that intrinsic efficacy is a single drug property independent of the system in which the drug acts. However, we now know that a drug, acting at a single receptor subtype, can have multiple intrinsic efficacies that differ depending on which of the multiple responses coupled to a receptor is measured. Thus, a drug can be simultaneously an agonist, an antagonist, and an inverse agonist acting at the same receptor. This means that drugs have an additional level of selectivity (signaling selectivity or "functional selectivity") beyond the traditional receptor selectivity. Both inverse agonism and functional selectivity need to be considered when drugs are used as medicines or as research tools.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165953PMC
http://dx.doi.org/10.1093/ijnp/pyy071DOI Listing

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