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The serotonin 5-HT6 receptor (5-HT6R), expressed almost exclusively in the brain, affects the Cdk5 signaling as well as the mTOR pathway. Due to the association of 5-HT6R signaling with pathways involved in cancer progression, we decided to check the usefulness of 5-HT6R ligands in the treatment of CNS tumors. For this purpose, a new group of low-base 5-HT6R ligands was developed, belonging to arylsulfonamide derivatives of cyclic arylguanidines. The selected group of molecules was also tested for their antiproliferative activity on astrocytoma (1321N1) and glioblastoma (U87MG, LN-229, U-251) cell lines. Some of the molecules were subjected to ADMET tests in vitro, including lipophilicity, drug binding to plasma proteins, affinity for phospholipids, drug–drug interaction (DDI), the penetration of the membrane (PAMPA), metabolic stability, and hepatotoxicity as well as in vivo cardiotoxicity in the Danio rerio model. Two antagonists with an affinity constant Ki < 50 nM (PR 68 Ki = 37 nM) were selected. These compounds were characterized by very high selectivity. An analysis of pharmacokinetic parameters for the lead compound PR 68 confirmed favorable properties for administration, including passive diffusion and acceptable metabolic stability (metabolized in 49%, MLMs). The compound did not exhibit the potential for drug–drug interactions. [ABSTRACT FROM AUTHOR]

This work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds 4a–l, via a convenient one-pot three-component Hantzsch reaction. This approach targeted calcium channel antagonism, antioxidant capacity, cathepsin S inhibition, and interference with Nrf2 transcriptional activation. Of these MTDLs, 4i emerged as a promising compound, demonstrating robust antioxidant activity, the ability to activate Nrf2-ARE pathways, as well as calcium channel blockade and cathepsin S inhibition. Dihydropyridine 4i represents the first example of an MTDL that combines these biological activities. [ABSTRACT FROM AUTHOR]

Daily living and functioning under stress can lead to mental health problems such as anxiety or depression. Over the past decades, a number of studies have been conducted to determine the relationship between the central nervous system (CNS), intestinal flora and bidirectional communication along the gut brain axis (GBA) in the maintaining of homeostasis. One of the most important factors regulating GBA functioning in exposure to stress may be a proper diet enriched in the supplementation with pre-, pro-and synbiotics. In the present study, we examined whether a 10-week oral preventive supplementation with natural prebiotics: topinambur powder (TPB) and chicory root inulin (INU) influenced an anxiety, depressive behavior and cognition in mice exposed to the chronic unpredictable mild stress (CUMS). Additionally, a fluoxetine (FLU) has been used as a reference antidepressive drug. Furthermore, we assessed the effect of TPB, INU and FLU administration on neurogenesis in mice exposed to CUMS and finally analyzed fecal microbiota for possible changes after TPB and INU supplementation in CUMS induced mice. Results obtained from the behavioral studies (elevated plaze maze, forced swim and Morris water maze test) indicated, that 10 week supplementation with TPB (250 mg/kg) and INU (66 mg/kg), similarly to FLU (12 mg/kg), significantly mitigated an anxiety and stress as well as protected learning and memory functions in the CUMS induced mice compared to the control stressed group. Additionally, TPB and INU CUMS mice showed significantly higher level of neurogenesis in comparison to control CUMS group. Interestingly, results obtained from the fecal microbiota analysis showed a beneficial effect of TPB and INU supplementation against CUMS-induced intestinal dysbiosis in mice. In conclusion, the obtained results showed that a long-term, preventive supplementation with TPB or INU alleviates the negative effects such as anxiety, cognitive disorders or dysbiosis in mice exposed to chronic unpredictable stress. [ABSTRACT FROM AUTHOR]

Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation Excitotoxicity is a common hallmark of epilepsy and other neurological diseases associated with elevated extracellular glutamate levels. Thus, here, we studied the protective effects of (R)‐AS‐1, a positive allosteric modulator (PAM) of glutamate uptake in epilepsy models.(R)‐AS‐1 was evaluated in a range of acute and chronic seizure models, while its adverse effect profile was assessed in a panel of standard tests in rodents. The effect of (R)‐AS‐1 on glutamate uptake was assessed in COS‐7 cells expressing the transporter. WAY 213613, a selective competitive EAAT2 inhibitor, was used to probe the reversal of the enhanced glutamate uptake in the same transporter expression system. Confocal microscopy and Western blotting analyses were used to study a potential influence of (R)‐AS‐1 on GLT‐1 expression in mice.(R)‐AS‐1 showed robust protection in a panel of animal models of seizures and epilepsy, including the maximal electroshock‐ and 6 Hz‐induced seizures, corneal kindling, mesial temporal lobe epilepsy, lamotrigine‐resistant amygdala kindling, as well as seizures induced by pilocarpine or Theiler's murine encephalomyelitis virus. Importantly, (R)‐AS‐1 displayed a favorable adverse effect profile in the rotarod, the minimal motor impairment, and the Irwin tests. (R)‐AS‐1 enhanced glutamate uptake in vitro and this effect was abolished by WAY 213613, while no influence on GLT‐1 expression in vivo was observed after repeated treatment.Collectively, our results show that (R)‐AS‐1 has favorable tolerability and provides robust preclinical efficacy against seizures. Thus, allosteric enhancement of EAAT2 function could offer a novel therapeutic strategy for treatment of epilepsy and potentially other neurological disorders associated with glutamate excitotoxicity. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

pH is an important physicochemical property that modulates proteins' structure and interaction patterns. A simple change in a site's protonation state in an enzyme's catalytic pocket can strongly alter its activity and its affinity to substrate, products, or inhibitors. We addressed this pH effect issue by evaluating its impact on donepezil binding to acetylcholinesterase (AChE). We compared the binding affinities obtained from molecular docking (weighted from the protonation states sampled by constant-pH MD) with those from molecular mechanics/Poisson-Boltzmann surface area and isothermal titration calorimetry data. The computational methods showed a clear trend where donepezil binding to the catalytic cavity is improved with the drug protonation (lowering pH). However, the loss of binding affinity observed experimentally at pH 6.0 indicates that other phenomena eluding our computational approaches are occurring. Possible factors include the shape of the access tunnel to the AChE catalytic pocket (which is captured in our MD time scale) or an entropic penalty difference between neutral and protonated donepezil. Altogether, this work highlighted the need to improve our computational methods to capture the pH effects in protein/drug binding, while also exposing the limitations that will inevitably arise from these new advances.

At present, one of the most promising strategies to tackle the complex challenges posed by Alzheimer's disease (AD) involves the development of novel multitarget-directed ligands (MTDLs). To this end, we designed and synthesized nine new MTDLs using a straightforward and cost-efficient one-pot Biginelli three-component reaction. Among these newly developed compounds, one particular small molecule, named 3e has emerged as a promising MTDL. This compound effectively targets critical biological factors associated with AD, including the simultaneous inhibition of cholinesterases (ChEs), selective antagonism of H 3 receptors, and blocking voltage-gated calcium channels. Additionally, compound 3e exhibited remarkable neuroprotective activity against H 2 O 2 and Aβ 1-40 , and effectively restored cognitive function in AD mice treated with scopolamine in the novel object recognition task, confirming that this compound could provide a novel and innovative therapeutic approach for the effective treatment of AD.

Background: Alzheimer's disease is a chronic neurodegenerative chronic disease with a heavy social and economic impact in our developed societies, which still lacks an efficient therapy. Method: This paper describes the Hantzsch multicomponent synthesis of twelve alkyl hexahydro-quinoline-3-carboxylates, 4a-l , along with the evaluation of their Ca 2+ channel blockade capacity, cholinesterase inhibition and antioxidant power. Results: Compound 4l  showed submicromolar inhibition of butyrylcholinesterase, Ca 2+ channel antagonism and an antioxidant effect. Conclusion: Compound 4l  is an interesting compound that deserves further investigation for Alzheimer's disease therapy.