First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT Agents with a Beneficial Neuroprotective Profile against Alzheimer's Disease.

Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT emerged as a promising target for AD treatment; thus, here a new series of 5-HTR ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HTR affinity and selectivity over 5-HTR (-), 5-HTR ( and ), and 5-HTR ().

Hydrophobicity modulation via the substituents at positions 2 and 4 of 1,3,5-triazine to enhance therapeutic ability against Alzheimer's disease for potent serotonin 5-HTR agents.

Alzheimer's disease (AD), a neurodegenerative disorder with a complex aetiology, is the most common memory dysfunction particularly affecting the elderly. Various protein targets have been classified to be involved in the AD treatment, including 5-HT receptor (5-HTR). So far, the 5-HTR ligands obtained by our research group have become a good basis for hydrophobicity modulation to give a chance for more effective action toward AD by additional influence on target enzymes, e.

Synthesis, computational and experimental pharmacological studies for (thio)ether-triazine 5-HTR ligands with noticeable action on AChE/BChE and chalcogen-dependent intrinsic activity in search for new class of drugs against Alzheimer's disease.

Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT receptor ligands.

Synthesis, computational simulations and biological evaluation of new dual 5HT/5HT receptor ligands based on purine-2,6-dione scaffold.

The new dual 5HT/5HT receptor ligands were designed based on the purine-2,6-dione scaffold with the fluorine atom. Twenty-one new derivatives were synthesized, and their structure-activity relationship was summarized. Compound 11 (7-(2-(3-fluorophenyl)-2-oxoethyl)-8-((4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)amino)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione) showed the highest affinity to 5HTR and 5HTR, and was the most potent antagonist of 5-HTR (K = 0.

Selective 5-HT Receptor Ligands (Agonist and Antagonist) Show Different Effects on Antipsychotic Drug-Induced Metabolic Dysfunctions in Rats.

It is estimated that in patients taking antipsychotic drugs (APDs), metabolic syndrome occurs 2-3 times more often than in the general population. It manifests itself in abdominal obesity, elevated glucose concentration, and dyslipidemia. Despite the high prevalence of this disorder, only a small percentage of patients receive appropriate and effective treatment, and none of the available methods for preventing or treating APD-induced metabolic side effects is satisfactory.

The association of gene polymorphisms with non-small lung cancer risk in smokers and never-smokers.

Introduction: Lung cancer is the predominant cause of death among cancer patients and non-small cell lung cancer (NSCLC) is the most common type. Cigarette smoking is the prevailing risk factor for NSCLC, nevertheless, this cancer is also diagnosed in never-smokers. B and T lymphocyte attenuator (BTLA) belongs to immunological checkpoints which are key regulatory molecules of the immune response.

Hybrid molecules combining GABA-A and serotonin 5-HT receptors activity designed to tackle neuroinflammation associated with depression.

There is clear evidence that the presence of inflammatory factors and impaired GABA-ergic neurotransmission in depressed patients is associated with poor clinical outcome. We designed hybrid molecules, bearing the GABA molecule assembled with chemical fragments that interact with the serotonin 5-HT receptor. Such a combination aimed to curb neuroinflammation, remodel GABA-ergic signaling, and provide antidepressant-like activity.

New, Eco-Friendly Method for Synthesis of 3-Chlorophenyl and 1,1'-Biphenyl Piperazinylhexyl Trazodone Analogues with Dual 5-HT/5-HT Affinity and Its Antidepressant-like Activity.

Serotonin 5-HT and 5-HT receptors play an important role in the pathogenesis and pharmacotherapy of depression. Previously identified -hexyl trazodone derivatives, 2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-]pyridin-3(2)-one hydrochloride (), with high affinity for 5-HTR and 2-(6-(4-([1,1'-biphenyl]-2-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-]pyridin-3(2)-one hydrochloride (), a dual-acting 5-HT/5-HT receptor ligand, were prepared with a new microwave-assisted method. The protocol for the synthesis of and involved reductive alkylation under a mild reducing agent.

HBK-15, a Multimodal Compound, Showed an Anxiolytic-Like Effect in Rats.

Anxiety is a common mental disorder, and its prevalence has lately increased because of the COVID-19 pandemic. Unfortunately, the available anxiolytics are often ineffective, and most possess addictive potential. Thus, searching for novel compounds is essential.

The Antidepressant-like Activity, Effects on Recognition Memory Deficits, Bioavailability, and Safety after Chronic Administration of New Dual-Acting Small Compounds Targeting Neuropsychiatric Symptoms in Dementia.

This study aimed to extend the body of preclinical research on prototype dual-acting compounds combining the pharmacophores relevant for inhibiting cyclic nucleotide phosphodiesterase 10 (PDE10A) and serotonin 5-HT/5-HT receptor (5-HTR/5-HTR) activity into a single chemical entity (compounds PQA-AZ4 and PQA-AZ6). After i.v.

Prevalence of uncoupling protein one genetic polymorphisms and their relationship with cardiovascular and metabolic health.

Contribution of UCP1 single nucleotide polymorphisms (SNPs) to susceptibility for cardiometabolic pathologies (CMP) and their involvement in specific risk factors for these conditions varies across populations. We tested whether UCP1 SNPs A-3826G, A-1766G, Ala64Thr and A-112C are associated with common CMP and their risk factors across Armenia, Greece, Poland, Russia and United Kingdom. This case-control study included genotyping of these SNPs, from 2,283 Caucasians.

Overcoming undesirable hERG affinity by incorporating fluorine atoms: A case of MAO-B inhibitors derived from 1 H-pyrrolo-[3,2-c]quinolines.

The incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26).

Design, synthesis, and behavioral evaluation of dual-acting compounds as phosphodiesterase type 10A (PDE10A) inhibitors and serotonin ligands targeting neuropsychiatric symptoms in dementia.

Neuropsychiatric symptoms (NPS), such as psychosis, depression and anxiety are frequently observed among patients with dementia. NPS is treated by off-label psychotropic medications that are only modestly effective in dementia patients, with a high risk of adverse events and cognitive decline. Considering the above, there is an unmet need for a well-tolerated and effective therapy of NPS in dementia.

An exit beyond the pharmacophore model for 5-HTR agents - a new strategy to gain dual 5-HT/5-HT action for triazine derivatives with procognitive potential.

This research allowed us to find the first highly potent 5-HT/5-HT receptor (5-HT/5-HTR) dual antagonists in a group of 1,3,5-triazine compounds as a result of an exit beyond the hydrophobic feature of the pharmacophore model for 5-HTR antagonists. Design and synthesis of the series (2-16) of new O- and S-containing ether derivatives of 1,3,5-triazines with the double-ring aromatic region have been performed. The new compounds were examined within the comprehensive pharmacological screening, including: radioligand binding assays, functional and ADMET studies in vitro as well as behavioral tests in rats.

The Phenoxyalkyltriazine Antagonists for 5-HT Receptor with Promising Procognitive and Pharmacokinetic Properties In Vivo in Search for a Novel Therapeutic Approach to Dementia Diseases.

Among the serotonin receptors, one of the most recently discovered 5-HT subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized.

Variation in the gene encoding the co-inhibitory molecule BTLA is associated with survival in patients treated for clear cell renal carcinoma - results of a prospective cohort study.

Introduction: The successful introduction of immune checkpoint blockade approaches to renal-cell carcinoma (RCC) treatment indicates the importance of molecules regulating the T cell response to RCC risk and progression.

Material And Methods: In this study, we evaluate the association of variations in the , and genes with overall survival (OS) of RCC patients and specifically clear cell RCC (ccRCC) patients. The following single nucleotide polymorphisms (SNPs) previously genotyped using the RFLP method or TaqMan SNP Genotyping Assays were analyzed: gene: c.

Multifunctional Arylsulfone and Arylsulfonamide-Based Ligands with Prominent Mood-Modulating Activity and Benign Safety Profile, Targeting Neuropsychiatric Symptoms of Dementia.

The current pharmaceutical market lacks therapeutic agents designed to modulate behavioral disturbances associated with dementia. To address this unmet medical need, we designed multifunctional ligands characterized by a nanomolar affinity for clinically relevant targets that are associated with the disease pathology, namely, the 5-HT and D receptors. Compounds that exhibited favorable functional efficacy, water solubility, and metabolic stability were selected for more detailed study.

A new class of 5-HT receptor antagonists with procognitive and antidepressant properties.

5-HT receptor antagonists constitute a potential group of drugs in the treatment of CNS diseases. The aim of this study was to search for new procognitive and antidepressant drugs among amide derivatives of aminoalkanoic acids with 5-HT receptor antagonistic properties. Thirty-three amides were designed and evaluated for their drug-likeness.

Effect of 5-HT Receptor Ligands Combined with Haloperidol or Risperidone on Antidepressant-/Anxiolytic-Like Behavior and BDNF Regulation in Hippocampus and Prefrontal Cortex of Rats.

Background: The presence of depressive and anxiety symptoms in patients with schizophrenia may have an important impact on treatment and compliance. Hence, interventions addressing such comorbidity in schizophrenia should be explored. One target may be a serotonergic 5-HT receptor (5-HTR) since its ligands displayed antidepressant- and anxiolytic-like activities in preclinical experiments.

Design and Synthesis of Novel Aminoalkanamides Targeting Neurodegeneration and Symptoms of Alzheimer's Disease.

Background: There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer's disease. Due to the increasing number of Alzheimer's patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties.

Objective: The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT/5-HT receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer's disease.

The antidepressant-like activity of chiral xanthone derivatives may be mediated by 5-HT1A receptor and β-arrestin signalling.

Background: Our previous studies showed that xanthone derivatives with -(2-methoxyphenyl)piperazine fragment have an affinity to the 5-HT1A receptor and show antidepressant-like properties in rodents. In this study, we tested three xanthone derivatives, HBK-1 and its enantiomers, in which we increased the distance between the piperazine and xanthone fragments by using a hydroxypropoxy linker. We hypothesized that this would increase the binding to the 5-HT1A receptor and consequently, pharmacological activity.

Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds and (2-methylaminophenoxyethyl and 2-(1-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct profiles. , showed biased agonism for ERK1/2 phosphorylation and, , it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats.

Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives.

In this study, a series of compounds derived from 4-methoxy-1-isoindole-1,3(2)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1-isoindole-1,3(2)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT and 5-HT receptor affinities. Based on in vitro studies, the most potent compound, (2-[4-(1-benzimidazol-2-yl)butyl]-4-methoxy-1-isoindole-1,3(2)-dione), was selected and its safety in vitro was evaluated.

Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1A receptor partial agonists.

Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Serotonin 5-HT1A receptor is considered as an interesting target of antidepressant therapy.