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

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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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