Opinion
Special issue: Allosterism and Collateral Efficacy
Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology

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The past decade has witnessed a dramatic increase in the identification of allosteric modulators of G-protein-coupled receptor (GPCR) activity. Concomitantly, several new perspectives and hypotheses regarding the way ligands regulate GPCR signalling have also emerged. Here, we briefly discuss how the concepts of collateral efficacy and permissive agonism–antagonism intersect the field of allosteric GPCR modulation. Despite the challenges associated with detecting and quantifying the myriad of possible allosteric effects on GPCR activity, it is proposed that allosteric ligands offer the exciting prospect of engendering stimulus-bias in orthosteric ligand signalling, thus paving the way for not only receptor-selective but also signalling-pathway-selective therapies.

Introduction

The seven-transmembrane-spanning G-protein-coupled receptors (GPCRs) account for >1% of the human genome and represent the targets for nearly 30% of all medicines currently on the market 1, 2. To date, the majority of identified drugs that target GPCRs interact with the receptor orthosteric site (i.e. the same domain recognized by the endogenous agonist for the receptor) [3] (see Glossary). Thus, the only possible mode of interaction between orthosteric ligands acting at a common receptor site is one of steric hindrance due to mutually exclusive binding. If receptor blockade is the desired functional endpoint, the administered orthosteric ligand should be a competitive antagonist or inverse agonist. If receptor stimulation is the therapeutic goal, the orthosteric drug should be an agonist, but one that will act in place of the endogenous agonist. In all cases, it is assumed that the quality of the signal generated by a given agonist is not influenced by the presence of another orthosteric ligand, although the magnitude of the signal might change. However, the past decade has witnessed a surge in the number of ligands that target GPCRs by binding to allosteric sites on the receptors (i.e. binding domains that are topographically distinct from the orthosteric site) [4]. The binding of an allosteric ligand to its site causes a conformational change in the receptor protein that is transmitted to the orthosteric site (and vice versa), in essence creating a ‘new’ GPCR with its own set of binding and functional properties. Unless this allosteric change is characterized by extremely high negative cooperativity, such that the orthosteric ligand can never bind to the new GPCR conformation induced by the modulator, the characteristic feature of the allosteric interaction is that the receptor will co-bind both an orthosteric and an allosteric ligand. Thus, allosteric ligands can introduce texture into pharmacological responses by modifying the affinity or the signal imparted to the receptor by the concomitant binding of the orthosteric ligand. This article focuses on the consequences of texture in GPCR responses and the implications of some of the newer concepts in pharmacology for the study of GPCR allosterism.

Section snippets

Allosteric GPCR ligands: modulators and agonists

Allosteric ligands are also called allosteric modulators because they can alter the binding affinity or the signal imparted to the cell by an orthosteric ligand. The simplest allosteric effect occurs when only the affinity of an orthosteric ligand for its receptor changes. An allosteric ternary complex model (ATCM) (Box 1) has been successfully used to quantify this behaviour in terms of the affinity of each ligand for its site on the unoccupied receptor, and the cooperativity factor (α), which

Collateral allosteric efficacy

Out of all of the receptor superfamilies, perhaps GPCRs exhibit the greatest array of behaviours. These include not only classic paradigms of GPCR activation, such as G-protein coupling and second-messenger activation, but also the formation of oligomeric complexes with other GPCRs or cellular proteins and the regulation of cell signalling via phosphorylation, internalization, desensitization and compartmentalization 20, 21, 22. All of these behaviours can be pharmacologically regulated and,

Permissive agonism and antagonism: the impact of probe dependence

Although a relatively new concept, collateral efficacy is not unique to allosteric ligands because most examples of the phenomenon have occurred during studies of orthosteric ligand effects. By contrast, the fact that allosteric modulators bind concomitantly with orthosteric ligands means that there are certain pharmacological behaviours that are specific to the allosteric arena. A dual-liganded GPCR is different from a receptor that is occupied by a single ligand; the stimulus imparted to the

Bringing it all together: allosterically engendering stimulus-bias

The idea of probe dependence in drug discovery places emphasis on the chemical nature of interacting ligands in a GPCR discovery programme. Because different results can arise as a consequence of different cooperativities between occupied orthosteric and allosteric sites, extra care and attention are necessary if switching from one orthosteric probe to another (even if the allosteric modulator remains the same) and interpreting the experimental results. However, the permissive nature of

Concluding remarks

The ability to allosterically regulate selected signalling pathways activated by the binding of an orthosteric agonist might be therapeutically beneficial. For instance, although inhibition of HIV-1 cellular entry can be achieved by promoting the internalization of the CCR5 GPCR, typical orthosteric CCR5 agonists are not clinically useful because of toxicity associated with overstimulation of the receptor. One approach could be to exploit collateral efficacy by designing small-molecule

Disclosure statement

A.C. and P.S. have received contracts from GlaxoSmithKline and Pfizer for the study of GPCR allosteric modulation. A.C. is a consultant for Bristol-Myers Squibb and Amgen, and is a member of the Scientific Advisory Board of Addex Pharmaceuticals.

Acknowledgements

A.C. is a Senior Research Fellow and P.S. is a Principal Research Fellow of the National Health and Medical Research Council (NHMRC) of Australia. Work in our laboratory is funded, in part, by NHMRC project grant number 400134.

Glossary

Allosteric agonist or inverse agonist
a ligand that binds to an allosteric site and causes receptor activation (allosteric agonist) or reduces constitutive receptor activity (allosteric inverse agonist) in the absence of an orthosteric ligand.
Allosteric modulator
a ligand that binds to an allosteric site and modulates the binding and/or signalling of an orthosteric ligand.
Allosteric site
a binding site on a receptor that is topographically distinct from the orthosteric site.
Collateral efficacy

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