The metabotropic glutamate receptor 2 (mGlu2) is a heavily studied therapeutic target in neuropsychiatry for which we anticipate a renewed interest in the near future. We review the rationale and the outcome of clinical trials with mGlu2/3 receptor agonists in schizophrenia, a field of intense research since a seminal publication by Patel and colleagues (2007). We summarize evidence about selective, potent and safe agents with quantifiable CNS penetration that can be used to test hypotheses of mGlu2 receptors involvement in neuropsychiatric diseases. We summarize lessons learned from previous programs that should be considered to maximize the probability of success when targeting orthosteric and allosteric enhancement of mGlu2 receptor function in schizophrenia and beyond. First, we propose expanding our focus beyond presynaptic mGlu2 receptor stimulation in schizophrenia to novel hypotheses and that the choice of a therapeutic indication no longer be dictated by commercial opportunity but following science as a driver. Second, evidence on internal validity of preclinical studies supporting efficacy claims in the mGlu2 field is very limited. This gap will need to be closed when reviewing the rationale to re-initiate efforts in this field. Third, the pomaglumetad program was halted due to insufficient clinical efficacy, partly because of the inability to identify a treatment responder population. In preclinical studies, effects of mGlu2/3 receptor stimulation also seemed to vary significantly between laboratories. Definition of the responsive subject population and development of response-predicting biomarkers is therefore one of the main avenues of further research in the mGlu2 field.

As a superfamily of membrane receptors, G-protein-coupled receptors (GPCRs) have significant roles in human physiological processes, including cell proliferation, metabolism, and neuromodulation. GPCRs are vital targets of therapeutic drugs, and their allosteric regulation represents a novel direction for drug discovery. Given the numerous breakthroughs in structural biology, diverse allosteric sites on GPCRs have been identified within the extracellular and intracellular loops, and the seven core transmembrane helices. However, a unique type of allosteric site has also been discovered at the interface of the receptor-lipid bilayer, similar to the β2-adrenergic receptor. Here, we review recent identifications of these allosteric sites and the detailed modulator-target interactions within the interface for each modulator to highlight the role of lipids in GPCR allosteric drug discovery.Copyright © 2020 Elsevier Ltd. All rights reserved. PMID: 33301977

We report the synthesis of the first series of heterobivalent ligands targeting the putative heteromeric 5-HT2A/mGlu2 receptor complex, based on the 5-HT2A antagonist MDL-100,907 and the mGlu2 ago-PAM JNJ-42491293. The functional properties of monovalent and heterobivalent ligands were characterized in 5-HT2A-, mGlu2/Gqo5-, 5-HT2A/mGlu2-, and 5-HT2A/mGlu2/Gqo5-expressing HEK293 cells using a Ca2+ imaging assay and a [3H]ketanserin binding assay. Pronounced functional crosstalk was observed between the two receptors in 5-HT2A/mGlu2 and 5-HT2A/mGlu2/Gqo5 cells. While the synthesized monovalent ligands retained the 5-HT2A antagonist and mGlu2 ago-PAM functionalities, the seven bivalent ligands inhibited 5-HT-induced responses in 5-HT2A/mGlu2 cells and both 5-HT- and Glu-induced responses in 5-HT2A/mGlu2/Gqo5 cells. However, no definitive correlation between the functional potency and spacer length of the ligands was observed, an observation substantiated by the binding affinities exhibited by the compounds in 5-HT2A, 5-HT2A/mGlu2, and 5-HT2A/mGlu2/Gqo5 cells. In conclusion, while functional crosstalk between 5-HT2A and mGlu2 was demonstrated, it remains unclear how these heterobivalent ligands interact with the putative receptor complex. PMID: 32815361

Cytochrome P450-dependent metabolism of the anti-HIV drug nevirapine (NVP) to 12-hydroxy-NVP (12-OHNVP) has been implicated in NVP toxicities. We investigated the impact of twelfth-position trideuteration (12-D3NVP) on the hepatic metabolism of and response to NVP. Formation of 12-OHNVP decreased in human (10.6-fold) and mouse (4.6-fold) hepatocytes incubated with 10 μM 12-D3NVP vs NVP. An observed kinetic isotope effect of 10.1 was measured in human liver microsomes. During mouse hepatocyte treatment (400 μM) with NVP or 12-D3NVP, cell death was reduced 30% with 12-D3NVP vs NVP, while glucuronidated and glutathione-conjugated metabolites increased with 12-D3NVP vs NVP. Using mass spectrometry proteomics, changes in hepatocyte protein expression, including an increase in stress marker insulin-like growth factor-binding protein 1 (IGFBP-1), were observed with 12-D3NVP vs NVP. These results demonstrate that while deuteration can reduce P450 metabolite formation, impacts on phase II metabolism and hepatocyte protein expression should be considered when employing deuteration to reduce P450 metabolite-related hepatotoxicity. PMID: 32065749

Targeting receptor proteins, such as ligand-gated ion channels and G protein-coupled receptors, has directly enabled the discovery of most drugs developed to modulate receptor signalling. However, as the search for novel and improved drugs continues, an innovative approach - targeting receptor complexes - is emerging. Receptor complexes are composed of core receptor proteins and receptor-associated proteins, which have profound effects on the overall receptor structure, function and localization. Hence, targeting key protein-protein interactions within receptor complexes provides an opportunity to develop more selective drugs with fewer side effects. In this Review, we discuss our current understanding of ligand-gated ion channel and G protein-coupled receptor complexes and discuss strategies for their pharmacological modulation. Although such strategies are still in preclinical development for most receptor complexes, they exemplify how receptor complexes can be drugged, and lay the groundwork for this nascent area of research. PMID: 33177699

Introduction Approximately 40% of Parkinson's disease (PD) patients that take mostly dopamine receptor agonists for motor fluctuations, experience the return of symptoms between regular doses. This is a phenomenon known as 'OFF periods.' Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) are a promising non-dopaminergic mechanism with potential to address the unmet need of patients suffering from OFF periods. Foliglurax is the first mGluR4 PAM that has advanced into clinical testing in PD patients. Areas covered We summarize the chemistry, pharmacokinetics, and preclinical pharmacology of foliglurax. Translational PET imaging studies, clinical efficacy data, and a competitive landscape analysis of available therapies are presented to the readers. In this Perspective article, foliglurax is used as a case study to illustrate the inherent R&D challenges that companies face when developing drugs. These challenges include the delivery of drugs acting through novel mechanisms, long-term scientific investment, and commercial success and shorter-term positive financial returns. Expert opinion Failure to meet the primary and secondary endpoints in a Phase 2 study led Lundbeck to discontinue the development of foliglurax. Understanding the evidence supporting compound progression into Phase 2 will enable the proper assessment of the therapeutic potential of mGluR4 PAMs.

Drug discovery research is a complex undertaking conducted by teams of scientists representing the different areas involved. In addition to a strong familiarity with existing knowledge, key relevant concepts remain unknown as activities start. This is often an accepted risk, mitigated by gaining understanding in real time as the project develops. Chemicals play a role in all biology studies conducted in the context of drug discovery, whether endogenously or exogenously added to the system under study. Furthermore, new knowledge often flourishes at the interface of existing areas of expertise. Due to differences in their training, adding a chemist's perspective to research teams would at least avoid potentially costly mistakes and ideally make any biology research richer. Thus, it would seem natural that one such team member be a chemist. Still, as that may not always be the case, we present some suggestions to minimize the risk of irreproducibility due to chemistry-related issues during biology research supporting drug discovery and make these efforts more robust and impactful. These include discussions on identity and purity, target and species selectivity, and chemical modalities such as orthosteric or allosteric small molecules or antibodies. Given the immense diversity of potential chemical/biological system interactions, we do not intend to provide a foolproof guide to conduct biological experimentation. Investigate at your own peril!