Ligand-selective receptor conformations revisited: the promise and the problem

doi:10.1016/S0165-6147(03)00167-6

Trends in Pharmacological Sciences

Volume 24, Issue 7, July 2003, Pages 346-354

https://doi.org/10.1016/S0165-6147(03)00167-6 Get rights and content

Abstract

Ligand-selective receptor conformations introduce the concept of ‘texture’ to drug effects, with respect to ligands possessing quality in addition to quantity of efficacy. This cell-dependent phenotypic efficacy extends to ligand properties beyond G-protein signaling and, in terms of drug development, presents a two-edged sword to pharmacologists. On the one hand, such efficacy promises more selective agonism but on the other hand it predicts problems associated with the use of recombinant or natural lead optimization assays as predictors of therapeutic value in humans. In this article, the evidence to suggest that not all agonists produce the same receptor active state is reviewed.

Section snippets

Agonist potency ratios and the conformational cafeteria

A precept of receptor pharmacology is that agonist potency ratios represent a unique identifier of receptors: that is, the rank order (actually the numeric potency ratio) of agonists is dependent on the molecular properties of affinity and efficacy and thus is a constant that transcends the experimental system containing the receptor. In fact, this idea was and still is used as a major pharmacological tool to characterize agonists and receptors. Before the advent of recombinant receptor

Efficacy dissociation

Defining efficacy as the property of a molecule that causes the receptor to change its behavior towards the host [2], there are numerous efficacies for molecules beyond the paradigm first described by Stephenson [20], namely the physiological G-protein-mediated response. Specifically, molecules can cause receptors to dimerize (or form larger receptor oligomers), to internalize, to be phosphorylated, to be desensitized and to interact with an increasing list of other membrane proteins [21].

The promise: phenotype-based selectivity

Ligand-selective receptor conformations open the possibility of designing drugs that modify only portions of a given receptor's behavior. Historically, selectivity has relied on the discovery of receptor subtypes (genotype-based selectivity). However, ligand selectivity based on receptor conformations opens the possibility of also exploiting receptor phenotypes (phenotype-based selectivity). In the drug discovery process for new agonists, often a partial profile surrogate agonist is the

The problem: phenotype trumps genotype

In the drug discovery process, the resources expended increase exponentially as development progresses. In this context it is crucial that accurate readings of the therapeutic relevance of a given drug activity be made as early as possible (i.e. primary and secondary assays must reflect the therapeutic significance). In view of GPCR pleiotropy with respect to G proteins and other membrane protein interactions, the stoichiometry and molecular composition of the human cell that is controlled by

Concluding remarks

In general, there is evidence to support the existence of ligand-selective receptor conformations. However, what remains to be established is the physiological relevance of the effect. On the one hand, the variety of different experimental approaches that can be used to demonstrate the phenomenon supports the notion that this might be a fairly widespread behavior among GPCRs. On the other hand, the number of actual receptors for which this has been demonstrated is limited. This might reflect

Acknowledgements

I am indebted to Brian Kobilka, Stanford University Medical School, for invaluable discussion of fluorescent lifetime spectroscopy and protein conformation and permission to use the data shown in Fig. 3.

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Trends in Pharmacological Sciences

Ligand-selective receptor conformations revisited: the promise and the problem

Abstract

Section snippets

Agonist potency ratios and the conformational cafeteria

Efficacy dissociation

The promise: phenotype-based selectivity

The problem: phenotype trumps genotype

Concluding remarks

Acknowledgements

Agonist-receptor efficacy II: agonist-trafficking of receptor signals

Trends Pharmacol. Sci.

Efficacy at G protein coupled receptors

Annu. Rev. Pharmacol. Toxicol.

Efficacy at G protein coupled receptors

Nat. Rev. Drug Discov.

Functionally different agonists induce distinct conformations in the G protein coupling domain of the beta(2) adrenergic receptor

J. Biol. Chem.

Predicting the equilibrium protein folding pathway: structure-based analysis of staphylococcal nuclease

Proteins

The structural distribution of cooperative interactions in proteins: analysis of the native state ensemble

Proc. Natl. Acad. Sci. U. S. A.

Hydrogen exchange and the dynamic structure of proteins

Mol. Cell. Biochem.

Is the slow-exchange core the protein folding core?

Trends Biochem. Sci.

Constitutive activation of the α1B-adrenergic receptor by all amino acid substitutions at a single site

J. Biol. Chem.

A mutation-induced activated state of the β2-adrenergic receptor: extending the ternary complex model

J. Biol. Chem.

The cubic ternary complex receptor-occupancy model. I. Model description

J. Theor. Biol.

The cubic ternary complex receptor-occupancy model. II. Understanding apparent affinity

J. Theor. Biol.

The cubic ternary complex receptor-occupancy model. III. Resurrecting efficacy

J. Theor. Biol.

Conformational changes and drug action

Fed. Proc.

Receptor conformational induction vs. selection: all part of the same energy landscape

Trends Pharmacol. Sci.

The use of stimulus-biased assay systems to detect agonist-specific receptor active states: implications for the trafficking of receptor stimulus by agonists

Mol. Pharmacol.

Differential G-protein activation by alkaloid and peptide agonists in the human neuroblastoma cell line SKE-N-BE

Biochem. J.

Protean agonists: keys to receptor active state?

Ann. N. Y. Acad. Sci.

The cholecystokinB receptor is coupled to two effector pathways through pertussis toxin-sensitive and –insensitive G proteins

J. Neurochem.

A modification of receptor theory

Br. J. Pharmacol.

G protein-coupled receptor interacting proteins: emerging roles in localization and signal transduction

Cell. Signal.

Inverse, protean, and ligand-selective agonism: matters of receptor conformation

FASEB J.

Multiple active states and oligermization of CCR5 revealed by functional properties of monoclonal antibodies

Mol. Biol. Cell

G-protein coupled receptor allosterism and complexing

Pharmacol. Rev.

Fluorescent labeling of purified β2-adrenergic receptor: evidence for ligand specific conformational changes

J. Biol. Chem.

A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity

Proc. Natl. Acad. Sci. U. S. A.

Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4: synthesis and structure–Activity relationships for 1-[N-(Methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidin-1-yl)butanes

Bioorg. Med. Chem. Lett.

SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo

Proc. Natl. Acad. Sci. U. S. A.

Chemokine receptors-the new frontier for aids research

Chem. Biol.

Bombesin and substance P analogues differentially regulate G-protein coupling to the bombesin receptor

J. Biol. Chem.

Amino-terminal modifications of human parathyroid hormone (PTH) selectively alter phospholipase C signaling via type 1 PTH receptor: Implications for design of signal-specific PTH ligands

Biochemistry

Agonist selective receptor states: the new level of selectivity?

Pharm. News

Differences in signal transduction of two 5-HT4 receptor splice variants: compound specificity and dual coupling with Gαs- and Gαi/o-proteins

Mol. Pharmacol.

Recombinant roulette versus the apparent virtues of ‘natural’ cell receptor systems: receptor genotypes vs phenotypes

Trends Pharmacol. Sci.

Differential signal transduction by five splice variants of the PACAP receptor

Nature

Constitutive activation of the α_1B-adrenergic receptor by all amino acid substitutions at a single site

Differences in signal transduction of two 5-HT₄ receptor splice variants: compound specificity and dual coupling with G_αs- and G_αi/o-proteins