Trends in Pharmacological Sciences
Ligand-selective receptor conformations revisited: the promise and the problem
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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