Schizophrenia is a major mental illness characterized by positive and negative symptoms, and by cognitive deficit. Although cognitive impairment is disabling for patients, it has been largely neglected in the treatment of schizophrenia. There are several reasons for this lack of treatments for cognitive deficit, but the complexity of its etiology—in which neuroanatomic, biochemical and genetic factors concur—has contributed to the lack of effective treatments. In the last few years, there have been several attempts to develop novel drugs for the treatment of cognitive impairment in schizophrenia. Despite these efforts, little progress has been made. The latest findings point to the importance of developing personalized treatments for schizophrenia which enhance neuroplasticity, and of combining pharmacological treatments with non-pharmacological measures.

In this study we developed a new translational phenotypic in vitro model for high-throughput screening (HTS) of novel analgesics for treating neuropathic pain, in order to address the poor translation of traditional recombinant models. The immortalized dorsal root ganglia (DRG) neuron-like F11 cell line was selected based on its phenotype after differentiation. The acquisition of neuronal characteristics was evaluated by measuring the expression of TrkA as a DRG neuron marker ( p < 0.01) as well as by measuring the global neurite length ( p < 0.001). The response of F11 cells to ATP and KCl was obtained by measuring intracellular calcium concentration, dynamic mass redistribution, and membrane potential. A KCl-induced increase of intracellular calcium levels was chosen as the readout because of the better signal quality, higher reproducibility, and greater compatibility with HTS assay requirements compared with other methods. The response to KCl differed significantly between differentiated and undifferentiated cells ( p < 0.05), with an EC50 value of 5 mM in differentiated cells. The model was validated by screening the Prestwick Chemical Library. Five hits already proposed for neuropathic-related pain were identified, with IC50 values between 1 and 7 µM. This cell model provides a new tool for screening novel analgesics for the relief of neuropathic pain.

Schizophrenia is a complex disease which is best treated with multitarget drugs, such as atypical antipsychotics. Previously, using structure-based virtual screening, we found a virtual hit, D2AAK1, with nanomolar affinity for dopamine and serotonin receptors important in schizophrenia pharmacotherapy. As a part of an optimization campaign of D2AAK1, we obtained 17 derivatives that also display a multitarget profile. Selected compounds were tested against off-targets in schizophrenia, i. e., histamine H 1 receptor and muscarinic M 1 receptor, and these did not display considerable affinity for these receptors. The two most promising compounds were subjected to behavioral studies. These compounds decreased amphetamineinduced hyperactivity in mice which indicates their antipsychotic potential. The compounds did not interfere with the memory consolidation in mice, as determined in the passive avoidance test. The favorable pharmacological profile of these compounds was rationalized using molecular modeling.

G9a is a lysine methyltransferase able to di-methylate lysine 9 of histone H3, promoting the repression of genes involved in learning and memory. Novel strategies based on synthesizing epigenetic drugs could regulate gene expression through histone post-translational modifications and effectively treat neurodegenerative diseases, like Alzheimer's disease (AD). Here, potential G9a inhibitors were identified using a structure-based virtual screening against G9a, followed by in vitro and in vivo screenings. First, screening methods with the AD transgenic Caenorhabditis elegans strain CL2006, showed that the toxicity/ function range was safe and recovered age-dependent paralysis. Likewise, we demonstrated that the best candidates direct target G9a by reducing H3 K9me2 in the CL2006 strain. Further characterization of these compounds involved the assessment of the blood-brain barrier-permeability and impact on amyloidβ aggregation, showing promising results. Thus, we present a G9a inhibitor candidate, F, with a novel and potent structure, providing both leads in G9a inhibitor design and demonstrating their participation in reducing AD pathology.

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The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.

Dantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newly synthesized compounds exhibited selectivity toward MAO B over either MAO A or AChE, with the secondary aldimine 9 and phenylhydrazone 20 attaining IC 50 values of 0.68 and 0.81 μM, respectively. While no general SAR trend was observed with lipophilicity descriptors, a molecular simplification strategy allowed the main pharmacophore features to be identified, which are responsible for the inhibitory activity toward MAO B. Finally, further in vitro investigations revealed cell protection from oxidative insult and activation of carnitine/ acylcarnitine carrier as concomitant biological activities responsible for neuroprotection by hits 9 and 20 and other promising compounds in the examined series.

Drug development is a complex process that requires multidisciplinary teamwork to overcome the uncertainty associated to the process. From this point, problem-based learning (PBL) methodologies are helpful to train future professionals dedicated to drug development in multidisciplinary environments. One of the strategies developed to design novel business models is Business Model Canvas (BMC), a strategy that has been widely employed in business schools, but not in scientific education. Thus, we wanted to verify if a BMC-like template was suitable for a PBL experience in the field of drug development using a blended-learning approach. The students of a research master subject were asked to create a joint project plan for the development of a novel drug for an unmet clinical need by making use of a BMC-like template as support for discussions on the project strategy, while combining online and face-to-face sessions. The methodology helped the students to learn about drug development, even in a blended-learning format. Most students considered that this methodology enhanced their participation in the working group and helped them to focus their arguments, proving that the employment of BMC-like templates is helpful to overcome the disadvantages of PBL experiences.