Metabotropic glutamate receptors belong to class C G-protein-coupled receptors and consist of eight subtypes that are ubiquitously expressed throughout the central nervous system. In recent years, the metabotropic glutamate receptor subtype 5 (mGlu5) has emerged as a promising target for a broad range of psychiatric and neurological disorders. Drug discovery programs targetting mGlu5 are primarily focused on development of allosteric modulators that interact with sites distinct from the endogenous agonist glutamate. Significant efforts have seen mGlu5 allosteric modulators progress into clinical trials; however, recent failures due to lack of efficacy or adverse effects indicate a need for a better understanding of the functional consequences of mGlu5 allosteric modulation. Biased agonism is an interrelated phenomenon to allosterism, describing how different ligands acting through the same receptor can differentially influence signaling to distinct transducers and pathways. Emerging evidence demonstrates that allosteric modulators can induce biased pharmacology at the level of intrinsic agonism as well as through differential modulation of orthosteric agonist-signaling pathways. Here, we present key considerations in the discovery and development of mGlu5 allosteric modulators and the opportunities and pitfalls offered by biased agonism and modulation.

Adenosine receptors are attractive therapeutic targets for multiple conditions, including ischemia-reperfusion injury and neuropathic pain. Adenosine receptor drug discovery efforts would be facilitated by the development of appropriate tools to assist in target validation and direct receptor visualization in different native environments. We report the development of the first bifunctional (chemoreactive and clickable) ligands for the adenosine A 1 receptor (A 1 R) and adenosine A 3 receptor (A 3 R) based on an orthosteric antagonist xanthine-based scaffold and on an existing structure−activity relationship. Bifunctional ligands were functional antagonists with nanomolar affinity and irreversible binding at the A 1 R and A 3 R. In-depth pharmacological profiling of these bifunctional ligands showed moderate selectivity over A 2A and A 2B adenosine receptors. Once bound to the receptor, ligands were successfully "clicked" with a cyanine-5 fluorophore containing the complementary "click" partner, enabling receptor detection. These bifunctional ligands are expected to aid in the understanding of A 1 R and A 3 R localization and trafficking in native cells and living systems.

Alzheimer’s disease (AD) is the most common dementia in the elderly and its increasing prevalence presents treatment challenges. Despite a better understanding of the disease, the current mainstay of treatment cannot modify pathogenesis or effectively address the associated cognitive and memory deficits. Emerging evidence suggests adenosine G protein-coupled receptors (GPCRs) are promising therapeutic targets for Alzheimer’s disease. The adenosine A1 and A2A receptors are expressed in the human brain and have a proposed involvement in the pathogenesis of dementia. Targeting these receptors preclinically can mitigate pathogenic β-amyloid and tau neurotoxicity whilst improving cognition and memory. In this review, we provide an accessible summary of the literature on Alzheimer’s disease and the therapeutic potential of A1 and A2A receptors. Although there are no available medicines targeting these receptors approved for treating dementia, we provide insights into some novel strategies, including allosterism and the targeting of oligomers, which may increase drug discovery success and enhance the therapeutic response.

No abstract

Allosteric modulators bind sites distinct from orthosteric ligands, allowing for improved spatiotemporal control of receptors and greater subtype selectivity. However, we recently showed that allosteric ligands previously classified as selective for select Class C G protein‐coupled receptors (GPCRs) had unappreciated activity at other off‐target receptors, in some cases higher affinity, within the class. Here, we extended our investigation of off‐target activity of “selective” allosteric ligands for the sweet taste receptor. Using metabotropic glutamate receptor 5 (mGlu5) as a representative of Class C GPCR, we assessed the sweet protein, monellin and the small‐molecule artificial sweetener, NHDC. We found that monellin, but not NHDC, is an agonist for mGlu5. Radioligand binding and functional assays performed in cells expressing N‐terminally truncated mGlu5 demonstrated that monellin agonism was not mediated via the “common” allosteric binding site in the transmembrane domain but required the presence of the large extracellular N‐terminal domain of mGlu5. Monellin displayed neutral functional cooperativity with orthosteric ligands. However, monellin positively modulated the mGlu5 PAM‐agonist, VU0424465, activity in intracellular calcium assays, but the interaction was neutral in inositol phosphate accumulation assays. Furthermore, monellin mGlu5 agonism was positively modulated by the mGlu5 pure PAM, VU0360172. Taken together, these data indicate that monellin is an allosteric agonist for mGlu5, binding to an allosteric binding site on the N‐terminus that is functionally linked to the common Class C GPCR allosteric site in a biased manner. This is the first evidence of a naturally derived proteinaceous allosteric ligand for the mGlu receptor family.