G Protein-coupled Receptors Allosteric Modulators Research Articles

Editorial [Hot Topic: The Pros of Not Being Competitive (Allosteric Modulation of GPCRs) (Guest Editors: Vincent Mutel and Bernhard Bettler)

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.

GPCR Drug Discovery: Novel Ligands for CNS Receptors

G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in humans. They convey extracellular signals into the cell interior by activating intracellular processes such as heterotrimeric G protein-dependent signaling pathways. They are widely distributed in the nervous system, and mediate key physiological processes including cognition, mood, appetite, pain and synaptic transmission. With at least 30% of marketed drugs being GPCR modulators, they are a major therapeutic target in the pharmaceutical industry's drug discovery programs. This review will survey recently patented ligands for GPCRs implicated in CNS disorders, in particular the metabotropic glutamate, adenosine and cannabinoid receptors. Metabotropic glutamate receptors regulate signaling by glutamate, the major excitatory brain neurotransmitter, while adenosine is a ubiquitous neuromodulater mediating diverse physiological effects. Recent patents for ligands of these receptors include mGluR5 antagonists and adenosine A(1) receptor agonists. Cannabinoid receptors remain one of the most important GPCR drug discovery target due to the intense interest in CB(1) receptor antagonists for treating obesity and metabolic syndrome. Such small molecule ligands are the outcome of the continuing focus of many pharmaceutical companies to identify novel GPCR agonist, antagonist or allosteric modulators useful for CNS disorders, for which more effective drugs are eagerly awaited.

Allosteric approaches to the targeting of G-protein-coupled receptors for novel drug discovery: A critical assessment

In recent years, the concept of allosteric modulation of G-protein-coupled receptors (GPCRs) has matured and now represents an increasingly viable approach to drug discovery. This is evident in the fact that allosteric modulators have been reported for every class of GPCR, and several are currently in clinical trials with one drug example approved and launched. The allosteric approach has been highlighted for the potential of identifying highly selective compounds with a minimal propensity to produce adverse effect. While much has been written regarding the promises of this approach, important challenges, caveats, and pitfalls exist that are often overlooked. Therefore, a balanced overview of the field that describes both the promises and the challenges of discovering allosteric modulators of GPCRs as novel drugs is presented.

Allosteric Modulation of G Protein–Coupled Receptors

The past decade has witnessed a significant growth in the identification of allosteric modulators of G protein-coupled receptors (GPCRs), i.e., ligands that interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Because of their ability to modulate receptor conformations in the presence of orthosteric ligand, allosteric modulators can "fine-tune" classical pharmacological responses. This is advantageous in terms of a potential for engendering greater GPCR subtype-selectivity, but represents a significant challenge for detecting and validating allosteric behaviors. Although allosteric sites need not have evolved to accommodate endogenous ligands, there are a number of examples of where such modulators have been shown to contribute to physiological or pathophysiological processes. Studies are also beginning to unravel the structural basis of allosteric modulation of GPCRs. It remains to be determined whether such modulation represents interactions within monomers versus across dimers.

Allosteric modulation of G protein-coupled receptors.

G protein-coupled receptors (GPCRs) constitute the largest receptor superfamily in the human genome and represent the most common targets of drug action. Classic agonist and antagonist ligands that act at GPCRs tend to bind to the receptor's orthosteric site, that is, the site recognized by the endogenous agonist for that receptor. However, it is now evident that GPCRs possess additional, extracellular, allosteric binding sites that can be recognized by a variety of small molecule modulator ligands. Allosteric modulators offer many advantages over classic orthosteric ligands as therapeutic agents, including the potential for greater GPCR-subtype selectivity and safety. However, the manifestations of allosterism at GPCRs are many and varied and, in the past, traditional screening methods have generally failed to detect many allosteric modulators. More recently, there have been a number of major advances in high throughput screening, including the advent of cell-based functional assays, which have led to the discovery of more allosteric modulator ligands than previously appreciated. In addition, a number of powerful analytical techniques have also been developed exclusively for detecting and quantifying allosteric effects, based on an increased awareness of various mechanisms underlying allosteric modulator actions at GPCRs. Together, these advances promise to change the current paucity of GPCR allosteric modulators in the clinical setting and yield novel therapeutic entities for the treatment of numerous disorders.