![]() To shed light on this issue, we performed brain slice electrophysiology experiments. This questions the mechanistic hypothesis that mGlu4 receptor PAMs should act at striatopallidal synapses to alleviate PD motor symptoms. However, literature data show that mGlu4 receptor PAMs have no effect at striatopallidal GABAergic synapses (unless combined with an orthosteric agonist) and on the firing activity of pallidal neurons, and fail to provide significant motor improvement in relevant PD models. In this context, mGlu4 receptor activation using either orthosteric agonists or positive allosteric modulators (PAMs) improves motor symptoms in rodent PD models in certain conditions. This is due in part to its localization at key basal ganglia (BG) synapses that become hyperactive in this pathology, particularly striatopallidal synapses. Metabotropic glutamate 4 (mGlu4) receptor is a promising target for the treatment of motor deficits in Parkinson's disease (PD). Finally, more precise treatment based on simultaneous administration of minimal doses of the ligands for two or more receptors, seems to be promising in the context of symptoms-specific schizophrenia treatment. The subject is still open for further research, and the novel classes of mGlu5 or mGlu2/3 agonists/PAMs were recently introduced, including the large group of compounds from the third group of mGlu receptors, especially of mGlu4 subtype. The lack of satisfactory effectiveness towards schizophrenia symptoms of mGlu2/3 activators in humans could be a result of variety of uncontrolled factors and unidentified biomarkers different for each schizophrenia patient, that should be taken into consideration in the future set of clinical trials. Although the results of clinical trials that were performed for the group of mGlu2/3 agonists were not so enthusiastic as in animal studies, they still showed that mGlu ligands do not induced variety of side effects typical for presently used antipsychotics, and were generally well tolerated. The number of preclinical trials clearly indicates, that this group of compounds constitutes an excellent alternative to presently used antipsychotic therapy, being effective not only to positive, but also negative and cognitive symptoms of schizophrenia. In this review, we aim to present, discuss and clarify our current understanding regarding the prediction of possible antipsychotic effects of metabotropic glutamate (mGlu) receptor ligands. Medicinal chemists are poised to have major influence in neuroscience drug research, and examples of areas of potential impact are presented, together with a discussion of the soft skills they bring to their project teams and why they have been so impactful. Recent progress in the oncology and neuroscience therapeutic areas is compared and contrasted, in particular looking at the biological target space and functional attributes of recently FDA-approved drugs and those in the late clinical pipeline. The optimal balance of resources and the right strategy to minimize the risk of late clinical failure may differ for different therapeutic indications. Historically, medicinal chemists have contributed to drug discovery teams in ways that synergize with those from their partner sciences, and help transform new knowledge into the ultimate tangible asset: a new drug. Society expects that the wave of contemporary new discoveries in biological sciences will soon lead to novel treatments for human diseases, including many devastating brain disorders. We present select examples of functional molecular fine-tuning of allosterism and discuss consequences relevant to drug design. Investigations using allosteric drug candidates and chemical tools suggest that their functional effects may be tailored with a high degree of translational alignment, making them molecular tools to correct pathophysiological functional tone and enable personalized medicine when a causative target-to-disease link is known. Membrane-bound proteins, particularly ion channels and G protein-coupled receptors (GPCRs), are biological targets prone to allosteric modulation. An accurate characterization of the functional effects following binding of a drug to its biological target is a fundamental step in the discovery of new medicines, informing the translation of preclinical efficacy and safety observations into human trials. Medicinal chemists are accountable for embedding the appropriate drug target profile into the molecular architecture of a clinical candidate.
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