The Pros of Not Being Competitive

Drugs acting at G-protein coupled receptors (GPCRs) represent the core of modern medicine. Traditionally, these drugs target the orthosteric site of the receptors, i.e. the binding site of the endogenous agonist. An increasing number of patents describe synthetic allosteric modulators of GPCRs, which influence receptor activity at sites distinct from the orthosteric site. This documents that the search for allosteric modulators of GPCRs has become a fully-fledged part of current drug discovery efforts. It is now generally accepted that allosteric modulation of GPCRs holds considerable promise for the development of novel therapeutics, but it has taken decades to persuade the skeptics of the advantages this concept has to offer. Allosteric modulation is now considered a valid strategy to obtain first generation therapeutics as well as second generation alternatives to currently available therapeutics. A key step towards broad exploration of the allosteric concept was the introduction of cell-based functional high-throughput screening assays for GPCRs, which have replaced radioligand binding assays as the primary screen for allosteric compounds. The reviews in this special issue, written by some of the leading scientists in the field, provide an overview of the experimental strategies used to identify and characterize allosteric modulators for Class A, B, and C GPCRs. There are a number of theoretical and practical reasons that support the notion that it is easier to obtain selective and/or effective therapies with allosteric modulators than with conventional competitive ligands. Most importantly, allosteric modulation enables the development of molecular entities that have no equivalent in the world of competitive ligands. With a range of allosteric compounds it is, in principle, possible to stabilize receptors in various biologically active conformations, which allows the chemical adjustment of receptor activity in more sophisticated ways than with orthosteric ligands. It is possible not only to identify allosteric ligands that act as positive or negative allosteric modulators of GPCR function, but also to identify allosteric ligands that act as agonists in their own right. Positive and negative allosteric modulators can affect both affinity and efficacy of the endogenous agonist, thereby significantly expanding the pharmacological repertoire for a given target. Allosteric modulation may sometimes also be the most straightforward way to identify small molecular weight compounds for targets that are already pharmacologically or clinically validated. This is particularly evident for Class B GPCRs, which are activated by peptide ligands and normally display poor chemical tractability. Allosteric modulation therefore offers the opportunity to …