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New Concepts in Drug Discovery: Collateral Efficacy and Permissive Antagonism

Key Points

  • The concepts that synthetic agonists need mimic natural agonists and that all antagonists must simply preclude agonist activation of receptors is challenged.

  • Previous ideas of linear efficacy whereby receptor activation by an agonist necessarily leads to initiation of all GPCR behaviors such as desensitization, phosphorylation, internalization and dimerization have given way in light of evidence to show that efficacy can be 'collateral', that is, some but not all GPCR behaviors can be produced by some agonists. Examples are given of signaling collateral efficacy where agonists preferentially activate some cellular pathways but not others (stimulus trafficking).

  • This idea naturally extends to concepts of how therapeutic targets should be screened for new molecular leads. Specifically, different types of assays might uncover different lead activity in the same library of compounds.

  • Evidence is presented that allosteric antagonists can be 'permissive', in that they block the signaling of some agonists but not others. The extension of this idea to the blockade of some GPCR-mediated pathological functions but not normal physiological functions leads to reconsideration of tractable therapeutic targets for GPCR antagonists.

  • The unique properties of permissive antagonists are discussed using the example of the new CCR5 allosteric HIV-1 entry inhibitor aplaviroc.

  • The distinction between the geometrical location of allosteric binding sites and allosteric effect is drawn; specifically, different allosteric effects can be produced by binding at a common allosteric site much like agonists have different efficacies binding to a single agonist binding site. In this case, 'efficacy' for allosteric antagonists is equated to the cooperativity constants for affinity and efficacy for GPCR agonist activation.

Abstract

New perspectives on the complexity of G-protein-coupled receptor (GPCR) signalling and the increased resolution of existing tools for studying GPCR behaviour has led to the conception of new hypotheses that affect the discovery of drugs acting at GPCRs. Taking into consideration the novel concepts of collateral efficacy and permissive antagonism in the search for synthetic agonists and antagonists, respectively, will be essential in the search for drugs with unique therapeutic profiles. Here, the design of drugs against HIV is used as an example of how these concepts might be taken into consideration for GPCR-targeted drugs in general.

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Figure 1: Linear versus collateral efficacy.
Figure 2: Texture in efficacy through selective assays.
Figure 3: Mechanisms of receptor modulation.
Figure 4: Selective inhibition of CXCR4 response to SDF1α by the antagonists AMD3100 and T140.
Figure 5: Selective blockade of 125I-MIP1α binding to CCR5 by the allosteric anti-HIV modulator 873140.
Figure 6: Muscarinic receptor activity of alkyltrimethylammonium compounds in guinea pig ileum.

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DATABASES

Entrez Gene

MIP1α

CCR1

CCR5

CXCR4

PTH

RANTES

SDF1α

OMIM

Alzheimer's disease

Glossary

RECEPTOR SUBTYPE

Major endogenous hormones and neurotransmitters activate families of receptors that are related by a general affinity for the endogenous agonist but which nevertheless can be distinguished by antagonists and synthetic agonists.

RECOMBINANT

DNA containing new genetic material is placed in surrogate cells that then express the relevant protein. Genetic engineering can be used to do this deliberately to produce receptor systems in surrogate cell lines for experimental testing.

PERMISSIVE ANTAGONISM

This term distinguishes allosteric modulators that demonstrate probe dependence — that is, allosteric modulators that block the response to some agonists but not others. Although all permissive antagonists must be allosteric, not all allosteric antagonists need be permissive.

EFFICACY

Historically, this term was given to agonists to define the property of the molecule that causes the production of physiological response. However, with the discovery of negative efficacy (inverse agonists) and efficacy related to other properties of receptors that do not involve physiological response, a more general definition of efficacy is that property of a molecule that causes the receptor to change its behaviour toward the host cell.

RECEPTOR OLIGOMERS (DIMERS)

GPCRs form large associated units comprising two receptors of the same type (homodimers), two different receptors (heterodimers) or multiple receptors (oligomers). These units can have new reactivity profiles with respect to ligands and cells.

INTERNALIZATION (ENDOCYTOSIS)

The natural process by which receptors are assimilated back into the cytosol of the cell to be degraded or processed and shuttled back to the cell surface.

COLLATERAL EFFICACY

Defining 'efficacy' as active biological results of ligand binding, GPCR drugs often have many efficacies resulting in changes in GPCR behaviour. Whereas 'linear' efficacy describes all such behaviours emanating from a single receptor binding event, 'collateral' efficacy describes selective not all-inclusive behaviours resulting from the binding of some ligands.

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). A technique that can be used to study GPCR conformational changes in living cells. This technique monitors the transfer of energy between two fluorophores bound in close proximity to each other and is sensitive to very small changes in distance (on the order of those that occur with changes in protein conformation).

BIOLUMINESCENCE RESONANCE ENERGY TRANSFER

(BRET). A technique used to directly monitor receptor–G-protein interaction in real time. This method monitors energy transfer between a bioluminescent donor and a fluorescent acceptor as the two are brought together through ligand activation.

ALLOSTERIC EFFECT

The imposition of an effect on a protein through interaction of a molecule with a site on the protein distinct from the natural binding locus for the endogenous ligand for that protein. The interactions between the allosteric molecule and the endogenous ligand occur through the protein and not through direct steric interaction.

ORTHOSTERIC EFFECT

Effect of a ligand through steric hindrance; the binding of one ligand precludes the binding of another because they require the same binding site.

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Kenakin, T. New Concepts in Drug Discovery: Collateral Efficacy and Permissive Antagonism. Nat Rev Drug Discov 4, 919–927 (2005). https://doi.org/10.1038/nrd1875

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