GPCR functional selectivity has therapeutic impact

Many in vitro data show that some ligands can cause the differential activation of signaling pathways mediated by a single receptor (termed ‘functional selectivity’). It remains unclear, however, whether functionally selective properties are meaningful in vivo. Data obtained with experimental compounds that are functionally selective at the dopamine D_2L receptor in vitro suggest that these properties might predict atypical behavioral actions. Moreover, the antipsychotic drug aripiprazole is commonly thought to be a D₂ partial agonist, but data clearly show that aripiprazole is functionally selective in vitro. It is proposed that the effects of aripiprazole in animal models and humans can be reconciled only with its functionally selective D₂ properties, not its partial D₂ agonism. Together, these data provide support for the hypothesis that compounds with functionally selective properties in vitro are likely to have novel actions in vivo, opening doors to new avenues of drug discovery.

Introduction

This issue of Trends in Pharmacological Sciences contains a series of outstanding theoretical pieces relating to new concepts about the functional actions of G-protein-coupled or seven-transmembrane receptors (GPCRs). Many laboratories have converged on this arena through studies of GPCRs or GPCR-related signaling mechanisms, and the articles in this issue provide an elegant commentary on some of the molecular mechanisms that now attract wide interest. This emerging research has led to reconsideration of some of the fundamental concepts of receptor pharmacology. For example, Violin and Lefkowitz (this issue) note that ‘until recently, drug efficacies for G-protein activations and β-arrestin recruitment were believed to be highly correlated, restricting 7TMR response to a linear range of effects from stimulatory to inhibitory’. Related to this idea was the notion that a drug acting through a single receptor could be categorized by its degree of linear response (i.e. a drug was an agonist, partial agonist or antagonist). This notion led to the concept of ‘intrinsic efficacy’, which describes the inherent functional properties of a drug at a specific target receptor [1]. Intrinsic efficacy should not be confused with operational terms such as ‘intrinsic activity’ [2] or ‘efficacy’ [3], which reflect the measured response in any particular receptor functional system.

Although the idea of intrinsic efficacy has been highly ingrained, more than a decade ago data began to emerge that were seemingly irreconcilable with this premise. In some situations, for example, the relative intrinsic activity of two partial agonists at two functional endpoints was reversed, and in others a single drug caused both full agonist and antagonist effects mediated by the same receptor (reviewed in Ref. [4]). This phenomenon has been given many different names 4, 5, but for the purposes of this article I refer to it as ‘functional selectivity.’

My laboratory was one of several that contemporaneously stumbled into this arena during our research on the most proximal aspect of receptor pharmacology – namely, how ligands interact with their targets and how ‘better’ ligands might be designed on the basis of such knowledge. Because our work focused on dopamine receptors, study of dopaminergic ligands offered the ‘benefit’ of commonly used behavioral assays with well-understood pharmacology. Thus, when we found unexpected behavioral effects of a drug with functionally selective properties in vitro, the profound pharmacological ramifications were immediately clear.

Our data impressed us sufficiently for me to say, at a meeting on dopamine receptors held in Ankara in 1996, that “…the ‘functional selectivity’ hypothesis [is] the concept that [some] drugs can cause functional multiplicity even when interacting with a single receptor isoform. The foundation of this hypothesis is extensive data showing that some drugs …can bind to a single receptor isoform, yet cause distinct functional changes depending on the cellular localization of the receptor–G-protein complex. …One mechanism for functional selectivity might be atypical conformation changes [when compared with the endogenous ligand] induced when such drugs bind to the receptor–G-protein complex. These distinct conformation changes force the dissociation of some, but not all, receptor–G-protein complexes (depending on the G protein to which the receptor is coupled). The particular types of G protein are dependent on both the type of cell and the location in the cell where the receptor of interest is located. Such functional targeting enables drug effects to be refined to a degree not possible just by targeting specific receptor isoforms. This could yield important therapeutic advances, although it introduces a new level of complexity that will require significantly greater understanding of receptor dynamics and the interaction with transduction mechanisms” [6].

A priori, I would like to explain why I favor the term ‘functional selectivity’ that we first used publicly in the early 1990s [7]. The existence and potential impact of functional selectivity were realized by many laboratories studying different receptor systems, most of whom became sufficiently engaged by their observations to coin their own term 4, 5. Functional selectivity appealed to us because it was operational and because it accommodated various mechanisms both proximal (related to the ligand and its receptor target) and distal (e.g. oligomerized receptors, G proteins, other signaling molecules and scaffolding proteins). Some terms (such as ‘trafficking’) imply mechanisms that might not always be relevant. Other phrases used the word ‘agonist’ (e.g. ‘protean agonist’ and ‘agonist trafficking’) and cannot accommodate those rarer situations when a ligand has both agonist and pure antagonist actions towards different functions mediated through a single receptor. My co-workers and I recently proffered an alterative name, ‘ligand-induced differential signaling’, with an easy acronym, ‘LIDS’, [4], but until the International Union of Basic and Clinical Pharmacology (IUPHAR) standardizes the terminology we will continue to use ‘functional selectivity’, knowing that it refers to phenomena discussed in this issue and elsewhere recently 4, 8.

Whatever the debate about terminology, the research summarized in this issue of TiPS should remove all doubt that functional selectivity is real and that the relevant mechanisms are intriguing. What might be less obvious is that functional selectivity also can provide a route to truly novel drugs that could not have been conceptualized from classical principles of pharmacology. Although iron-clad mechanistic proof for this assertion is not yet in hand, as I describe here an experimental trail that began in the late 1980s has convinced me that functional selectivity will profoundly influence drug discovery.