First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 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-HT6 emerged as a promising target for AD treatment; thus, here a new series of 5-HT6R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT6R affinity and selectivity over 5-HT1AR (13-15), 5-HT7R (14 and 15), and 5-HT2AR (13). Compound 15 displayed high selectivity for 5-HT6R over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound 15 also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and glutathione peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, 15 showed satisfying pharmacokinetics, penetrated the blood-brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 15's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.

The Subtype Selectivity in Search of Potent Hypotensive Agents among 5,5-Dimethylhydantoin Derived α1-Adrenoceptors Antagonists.

In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (1-15) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds 7-9. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α1-adrenergic receptors (α1-AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α1-adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α1A and α1B, was conducted. Selected compounds were tested for their activity towards two α1-AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds (1 and 5), which possess o-methoxyphenylpiperazine fragments, strong activity (IC50 < 100 nM) was observed. Some representatives (3 and 5), which contain alkyl linker, proved selectivity towards α1A-AR, while two compounds with 2-hydroxypropyl linker (11 and 13) to α1B-AR. Finally, hypotensive activity was examined in rats. The most active compound (5) proved not only a lower effective dose than urapidil but also a stronger effect than prazosin.

Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains.

In this study, a search for new therapeutic agents that may improve the antibacterial activity of conventional antibiotics and help to successfully overcome methicillin-resistant Staphylococcus aureus (MRSA) infections has been conducted. The purpose of this work was to extend the scope of our preliminary studies and to evaluate the adjuvant potency of new derivatives in a set of S. aureus clinical isolates. The study confirmed the high efficacy of piperazine derivatives of 5-arylideneimidazol-4-one (7-9) tested previously, and it enabled the authors to identify even more efficient modulators of bacterial resistance among new analogs. The greatest capacity to enhance oxacillin activity was determined for 1-benzhydrylpiperazine 5-spirofluorenehydantoin derivative (13) which, at concentrations as low as 0.0625 mM, restores the effectiveness of ß-lactam antibiotics against MRSA strains. In silico studies showed that the probable mechanism of action of 13 is related to the binding of the molecule with the allosteric site of PBP2a. Interestingly, thiazole derivatives tested were shown to act as both oxacillin and erythromycin conjugators in S. aureus isolates, suggesting a complex mode of action (i.e., influence on the Msr(A) efflux pump). This high enhancer activity indicates the high potential of imidazolones to become commercially available antibiotic adjuvants.

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-HT6R 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-HT6 receptor (5-HT6R). So far, the 5-HT6R 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.g. cyclin-dependent kinase 5 (CDK5). In the search for 5-HT6R agents with additional inhibitory action on the enzyme, a series of 25 new 1,3,5-triazines (7-31) as modifications of lead, 4-[1-(2,5-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-amine (6), was rationally designed. Molecular modelling, synthesis, crystallographic studies, in vitro biological assays and behavioral studies in vivo were performed. The new triazines showed high affinity (Ki < 100 nM) and selectivity for 5-HT6R. The most effective one, 4-[1-(2,5-difluorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-amine (8), exhibited the strong antagonistic action towards 5-HT6R (Ki = 5 nM, pKb = 8.16), had an impact on the memory processes in the Novel Object Recognition test and displayed anxiolytic-like activity in the Elevated Plus Maze test in rats. Moreover, it had the antiplatelet effect as well as very good permeability (PAMPA model), high metabolic stability (RLMs) and satisfactory safety in vitro. Although the CDK5 inhibitory effects in vitro for the tested compounds (8, 10, 14, 18, 26-31) missed the potency expected from in silico simulations, the novel antagonist (8) with a very satisfying pharmacological and ADMET profile can serve as a new lead structure in further searches for innovative therapy against AD with accompanying symptoms.

Synthesis, computational and experimental pharmacological studies for (thio)ether-triazine 5-HT6R 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-HT6 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-HT6 receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (Ki < 200 nM) and selectivity towards 5-HT6R, with respect to 5-HT2AR, 5-HT7R, and D2R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT6 agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT6 (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives.

Discovery of novel arylpiperazine-based DA/5-HT modulators as potential antipsychotic agents - Design, synthesis, structural studies and pharmacological profiling.

Schizophrenia is a mental disorder with a complex pathomechanism involving many neurotransmitter systems. Among the currently used antipsychotics, classical drugs acting as dopamine D2 receptor antagonists, and drugs of a newer generation, the so-called atypical antipsychotics, can be distinguished. The latter are characterized by a multi-target profile of action, affecting, apart from the D2 receptor, also serotonin receptors, in particular 5-HT2A and 5-HT1A. Such profile of action is considered superior in terms of both efficacy in treating symptoms and safety. In the search for new potential antipsychotics of such atypical receptor profile, an attempt was made to optimize the arylpiperazine based virtual hit, D2AAK3, which in previous studies displayed an affinity for D2, 5-HT1A and 5-HT2A receptors, and showed antipsychotic activity in vivo. In this work, we present the design of D2AAK3 derivatives (1-17), their synthesis, and structural and pharmacological evaluation. The obtained compounds show affinities for the receptors of interest and their efficacy as antagonists/agonists towards them was confirmed in functional assays. For the selected compound 11, detailed structural studies were carried out using molecular modeling and X-ray methods. Additionally, ADMET parameters and in vivo antipsychotic activity, as well as influence on memory and anxiety processes were evaluated in mice, which indicated good therapeutic potential and safety profile of the studied compound.

Relationships between Molecular Characteristics of Novel Organic Selenium Compounds and the Formation of Sulfur Compounds in Selenium Biofortified Kale Sprouts.

Due to problems with selenium deficiency in humans, the search for new organic molecules containing this element in plant biofortification process is highly required. Selenium organic esters evaluated in this study (E-NS-4, E-NS-17, E-NS-71, EDA-11, and EDA-117) are based mostly on benzoselenoate scaffolds, with some additional halogen atoms and various functional groups in the aliphatic side chain of different length, while one compound contains a phenylpiperazine moiety (WA-4b). In our previous study, the biofortification of kale sprouts with organoselenium compounds (at the concentrations of 15 mg/L in the culture fluid) strongly enhanced the synthesis of glucosinolates and isothiocyanates. Thus, the study aimed to discover the relationships between molecular characteristics of the organoselenium compounds used and the amount of sulfur phytochemicals in kale sprouts. The statistical partial least square model with eigenvalues equaled 3.98 and 1.03 for the first and second latent components, respectively, which explained 83.5% of variance in the predictive parameters, and 78.6% of response parameter variance was applied to reveal the existence of the correlation structure between molecular descriptors of selenium compounds as predictive parameters and biochemical features of studied sprouts as response parameters (correlation coefficients for parameters in PLS model in the range-0.521 ÷ 1.000). This study supported the conclusion that future biofortifiers composed of organic compounds should simultaneously contain nitryl groups, which may facilitate the production of plant-based sulfur compounds, as well as organoselenium moieties, which may influence the production of low molecular weight selenium metabolites. In the case of the new chemical compounds, environmental aspects should also be evaluated.

New Triazine Derivatives as Serotonin 5-HT6 Receptor Ligands.

Since the number of people with Alzheimer's disease (AD) continues to rise, new and effective drugs are urgently needed to not only slow down the progression of the disease, but to stop or even prevent its development. Serotonin 5-HT6 receptor (5-HT6R) ligands are still a promising therapeutic target for the treatment of AD. 1,3,5-Triazine derivatives, as novel structures lacking an indole or a sulfone moiety, have proven to be potent ligands for this receptor. In present work, new derivatives of the compound MST4 (4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine), the potent 5-HT6R antagonist (Ki = 11 nM) with promising ADMET and in vivo properties, were designed. The synthesized compounds were tested for their affinity towards 5-HT6R and other receptor (off)targets (serotonin 5-HT2A, 5-HT7 and dopamine D2). Based on the new results, 4-(2-tert-butylphenoxy)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) was selected for extended in vitro studies as a potent and selective 5-HT6R ligand (Ki = 13 nM). Its ability to permeate the blood-brain barrier (BBB) and its hepatotoxicity were evaluated. In addition, X-ray crystallography and solubility studies were also performed. The results obtained confirm that 6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine derivatives, especially compound 3, are promising structures for further pharmacological studies as 5-HT6R ligands.

To Cut the Mustard: Antimicrobial Activity of Selenocyanates on the Plate and in the Gas Phase.

Organic selenocyanates (RSeCN) are among the most reactive and biologically active Se species, often exhibiting a pronounced cytotoxic activity against mammalian cells and microorganisms. Various aromatic selenocyanates have been synthesized and, similar to some of the most Reactive Sulfur Species (RSS), such as allicin, found to be active against a range of bacteria, including Escherichia coli, Pseudomonas syringae and Micrococcus luteus, and fungi, including Verticillium dahlia, Verticillium longisporum, Alternaria brassicicola, and Botrytis cinerea, even via the gas phase. The highest antimicrobial activity has been observed for benzyl selenocyanate, which inhibited the growth of all bacteria considerably, even at the lowest tested concentration of 50 µM. Notably, neither the analogues thiocyanate (BTC) nor isothiocyanate (BITC) show any of these activities, rendering this selenium motif rather special in activity and mode of action. Eventually, these findings advocate a range of potential applications of organic selenocyanates in medicine and agriculture.

Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes.

Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT2A receptors are known for an extremely long LSD residence time, enabling minute doses to exert a long-lasting effect. In this work, we explore the changes in anxiety-like processes induced by the previously reported antipsychotic, D2AAK1. In vivo studies revealed that the effect of D2AAK1 on the anxiety is mediated through serotonin 5-HT1A and 5-HT2A receptors, and that it is time-dependent (anxiogenic after 30 min, anxiolytic after 60 min) and dose-dependent. The funnel metadynamics simulations suggest complicated ligand-5HT2AR interactions, involving an allosteric site located under the third extracellular loop, which is a possible explanation of the time-dependency. The binding of D2AAK1 at the allosteric site results in a broader opening of the extracellular receptor entry, possibly altering the binding kinetics of orthosteric ligands.

Seleno-vs. thioether triazine derivatives in search for new anticancer agents overcoming multidrug resistance in lymphoma.

Lymphomas are still difficult to treat even with modern therapies as, among others, multidrug resistance (MDR) is often counteracting a successful cancer therapy. P-gp/ABC-transporters are well-known for their crucial role in the main tumour MDR mechanism, eliminating drugs and cytotoxic substances from the cancer cell by efflux, and their modulators are promising for innovative therapy, but none has been approved in the pharmaceutical market yet. Herein, we have designed, synthesised and analysed 30 novel seleno- and thioether 1,3,5-triazine derivatives conducting comprehensive studies to evaluate their potential application in human JURKAT lymphoma cells. Among the new compounds, four (11, 12, 13 and 23) were much more effective than the reference inhibitor verapamil, being potent ABCB1 inhibitors already at 2 µM, while 5 and 15 showed very potent ABCB1 inhibitory activity only at 20 µM. Results of P-gp ATPase assays, supported with docking studies, indicated the competitive substrate mode of modulating action for 15, while ABCB1, ABCC1 and ABCG2 genes expression induction by 15 with q-PCR was confirmed. All compounds were evaluated for their cytotoxic and antiproliferative properties in both sensitive (PAR) and resistant (MDR) mouse T-lymphoma cell lines, and compound 15, also considering its promising ABCB1 inhibition properties, was revealed to be the best compound in terms of its cytotoxic effect (IC50: 16.73 µM) as well as concerning the antiproliferative effect (IC50: 5.35 µM) in MDR cells. Regarding the mechanistic studies looking at the cell cycle, the thioether 15 and selenium derivatives 26 and 29 were significantly effective in the regulation of cell cycle-related genes alone or in co-treatment with doxorubicin counteracting Cyclin D1 and E1 expression and increasing p53 and p21 levels, shedding first light on their mechanism of action. In summary, we explored the chemical space of seleno- and thioether 1,3,5-triazine derivatives with interesting activity against lymphoma. Especially compound 15 is worthy of being studied deeper to evaluate its precise mode of action further as well it can be improved regarding its potency and drug-likeness.

Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer's Disease: Can It Work from a Molecular Point of View?

In view of the unsatisfactory treatment of cognitive disorders, in particular Alzheimer's disease (AD), the aim of this review was to perform a computer-aided analysis of the state of the art that will help in the search for innovative polypharmacology-based therapeutic approaches to fight against AD. Apart from 20-year unrenewed cholinesterase- or NMDA-based AD therapy, the hope of effectively treating Alzheimer's disease has been placed on serotonin 5-HT6 receptor (5-HT6R), due to its proven, both for agonists and antagonists, beneficial procognitive effects in animal models; however, research into this treatment has so far not been successfully translated to human patients. Recent lines of evidence strongly emphasize the role of kinases, in particular microtubule affinity-regulating kinase 4 (MARK4), Rho-associated coiled-coil-containing protein kinase I/II (ROCKI/II) and cyclin-dependent kinase 5 (CDK5) in the etiology of AD, pointing to the therapeutic potential of their inhibitors not only against the symptoms, but also the causes of this disease. Thus, finding a drug that acts simultaneously on both 5-HT6R and one of those kinases will provide a potential breakthrough in AD treatment. The pharmacophore- and docking-based comprehensive literature analysis performed herein serves to answer the question of whether the design of these kind of dual agents is possible, and the conclusions turned out to be highly promising.

Structure Prediction, Evaluation, and Validation of GPR18 Lipid Receptor Using Free Programs.

The GPR18 receptor, often referred to as the N-arachidonylglycine receptor, although assigned (along with GPR55 and GPR119) to the new class A GPCR subfamily-lipid receptors, officially still has the status of a class A GPCR orphan. While its signaling pathways and biological significance have not yet been fully elucidated, increasing evidence points to the therapeutic potential of GPR18 in relation to immune, neurodegenerative, and cancer processes to name a few. Therefore, it is necessary to understand the interactions of potential ligands with the receptor and the influence of particular structural elements on their activity. Thus, given the lack of an experimentally solved structure, the goal of the present study was to obtain a homology model of the GPR18 receptor in the inactive state, meeting all requirements in terms of protein structure quality and recognition of active ligands. To increase the reliability and precision of the predictions, different contemporary protein structure prediction methods and software were used and compared herein. To test the usability of the resulting models, we optimized and compared the selected structures followed by the assessment of the ability to recognize known, active ligands. The stability of the predicted poses was then evaluated by means of molecular dynamics simulations. On the other hand, most of the best-ranking contemporary CADD software/platforms for its full usability require rather expensive licenses. To overcome this down-to-earth obstacle, the overarching goal of these studies was to test whether it is possible to perform the thorough CADD experiments with high scientific confidence while using only license-free/academic software and online platforms. The obtained results indicate that a wide range of freely available software and/or academic licenses allow us to carry out meaningful molecular modelling/docking studies.

2-{5-[(Z,2Z)-2-Chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}-3-methylbutanoic Acid as a Potential Anti-Breast Cancer Molecule.

It was established that the synthesis of hybrid molecules containing a thiazolidinone and a (2Z)-2-chloro-3-(4-nitrophenyl)prop-2-ene structural fragments is an effective approach for the design of potential anticancer agents. Given the results of the previous SAR-analysis, the aim of the study was to synthesize a novel 4-thiazolidinone derivative Les-3331 and investigate its molecular mechanism of action in MCF-7 and MDA-MB-231 breast cancer cells. The cytotoxic properties and antiproliferative potential of Les-3331 were determined. The effect of the tested compound on apoptosis induction and mitochondrial membrane potential was checked by flow cytometry. ELISA was used to determine caspase-8 and caspase-9, LC3A, LC3B, Beclin-1, and topoisomerase II concentration. Additionally, PAMPA, in silico or in vitro prediction of metabolism, CYP3A4/2D6 inhibition, and an Ames test were performed. Les-3331 possesses high cytotoxic and antiproliferative activity in MCF-7 and MDA-MB-231 breast cancer cells. Its molecular mechanism of action is associated with apoptosis induction, decreased mitochondrial membrane potential, and increased caspase-9 and caspase-8 concentrations. Les-3331 decreased LC3A, LC3B, and Beclin-1 concentration in tested cell lines. Topoisomerase II concentration was also lowered. The most probable metabolic pathways and no DDIs risk of Les-3331 were confirmed in in vitro assays. Our studies confirmed that a novel 4-thiazolidinone derivative represents promising anti-breast cancer activity.

An exit beyond the pharmacophore model for 5-HT6R agents - a new strategy to gain dual 5-HT6/5-HT2A action for triazine derivatives with procognitive potential.

This research allowed us to find the first highly potent 5-HT6/5-HT2A receptor (5-HT6/5-HT2AR) 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-HT6R 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. Crystallographic aspects and computer-aided structure-activity relationship were analyzed, as well. The comprehensive approach led to selection of compound 12 (4-(4-methylpiperazin-1-yl)-6-(2-(naphthalen-2-ylthio)propan-2-yl)-1,3,5-triazin-2-amine) with the most significant dual 5-HT6/5-HT2AR antagonistic action (5-HT6R Ki = 11 nM, 5-HT2AR Ki = 39 nM). Moreover, the compound 12 has satisfactory ADMETox properties in vitro, i.e.: the high permeability through biological membranes, high metabolic stability, neither mutagenic nor hepatotoxic effects, and moderate ability to inhibit CYP3A4. Above all, 12 showed ability to reverse the pharmacologically-induced (MK-801) memory impairment at low doses (1-3 mg/kg) in Novel Object Recognition (NOR) test in rats. Our results indicate a promising potency of dual 5-HT6/5-HT2AR antagonism in the search for novel strategy to fight Alzheimer's disease, which remains an unmet clinical need.

Pharmaceutical and Safety Profile Evaluation of Novel Selenocompounds with Noteworthy Anticancer Activity.

Prior studies have reported the potent and selective cytotoxic, pro-apoptotic, and chemopreventive activities of a cyclic selenoanhydride and of a series of selenoesters. Some of these selenium derivatives demonstrated multidrug resistance (MDR)-reversing activity in different resistant cancer cell lines. Thus, the aim of this study was to evaluate the pharmaceutical and safety profiles of these selected selenocompounds using alternative methods in silico and in vitro. One of the main tasks of this work was to determine both the physicochemical properties and metabolic stability of these selenoesters. The obtained results proved that these tested selenocompounds could become potential candidates for novel and safe anticancer drugs with good ADMET parameters. The most favorable selenocompounds turned out to be the phthalic selenoanhydride (EDA-A6), two ketone-containing selenoesters with a 4-chlorophenyl moiety (EDA-71 and EDA-73), and a symmetrical selenodiester with a pyridine ring and two selenium atoms (EDA-119).

Benzophenone Derivatives with Histamine H3 Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer's Disease.

The multitarget-directed ligands demonstrating affinity to histamine H3 receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective treatment of Alzheimer's disease. In this study, a novel series of benzophenone derivatives was designed and synthesized. Among these derivatives, we identified compound 6 with a high affinity for H3R (Ki = 8 nM) and significant inhibitory activity toward BuChE (IC50 = 172 nM and 1.16 µM for eqBuChE and hBuChE, respectively). Further in vitro studies revealed that compound 6 (4-fluorophenyl) (4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)methanone) displays moderate metabolic stability in mouse liver microsomes, good permeability with a permeability coefficient value (Pe) of 6.3 × 10-6 cm/s, and its safety was confirmed in terms of hepatotoxicity in the HepG2 cell line. Therefore, we investigated the in vivo activity of compound 6 in the Passive Avoidance Test and the Formalin Test. While compound 6 did not show a statistically significant influence on memory and learning, it showed analgesic properties in both acute (ED50 = 20.9 mg/kg) and inflammatory (ED50 = 17.5 mg/kg) pain.

Histamine H3 Receptor Ligands-KSK-59 and KSK-73-Reduce Body Weight Gain in a Rat Model of Excessive Eating.

Noting the worldwide rapid increase in the prevalence of overweight and obesity new effective drugs are now being sought to combat these diseases. Histamine H3 receptor antagonists may represent an effective therapy as they have been shown to modulate histamine synthesis and release and affect a number of other neurotransmitters (norepinephrine, acetylcholine, γ-aminobutyric acid, serotonin, substance P) thus influencing the food intake. Based on the preliminary studies determining affinity, intrinsic activity, and selected pharmacokinetic parameters, two histamine H3 receptor ligands were selected. Female rats were fed palatable food for 28 days and simultaneously administered the tested compounds intraperitoneally (i.p.) at a dose of 10 or 1 mg/kg b.w./day. Weight was evaluated daily and calorie intake was evaluated once per week. The plasma levels of cholesterol, triglycerides, leptin, adiponectin, ghrelin, corticosterone, CRP and IL-6 were determined at the end of experiment. The glucose tolerance test was also performed. To exclude false positives, the effect of tested compounds on spontaneous activity was monitored during the treatment, as well as the amount of consumed kaolin clay was studied as a reflection of possible gastrointestinal disturbances comparable to nausea. The histamine H3 receptor antagonists KSK-59 and KSK-73 administered i.p. at a dose of 10 mg/kg b.w. prevented weight gain in a rat model of excessive eating. They reduced adipose tissue deposits and improved glucose tolerance. Both compounds showed satisfying ability to penetrate through biological membranes determined in in vitro studies. Compound KSK-73 also reduced the caloric intake of the experimental animals what indicates its anorectic effect. These results show the pharmacological properties of histamine H3 receptor antagonists, (4-pyridyl)piperazine derivatives, as the compounds causing not only slower weight gain but also ameliorating some metabolic disorders in rats having the opportunity to overeat.

The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives.

Several studies confirmed the reciprocal interactions between adrenergic and serotoninergic systems and the influence of these phenomena on the pathogenesis of anxiety. Hence, searching for chemical agents with a multifunctional pharmacodynamic profile may bring highly effective therapy for CNS disorders. This study presents a deep structural insight into the hydantoin-arylpiperazine group and their serotonin/α-adrenergic activity. The newly synthesized compounds were tested in the radioligand binding assay and the intrinsic activity was evaluated for the selected derivatives. The computer-aided SAR analysis enabled us to answer questions about the influence of particular structural fragments on selective vs. multifunctional activity. As a result of the performed investigations, there were two leading structures: (a) compound 12 with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent; (b) compound 14 with high α1A/α1D affinity and selectivity towards α1B, which is recommended due to the elimination of probable cardiotoxic effect. The structural conclusions of this work provide significant support for future lead optimization in order to achieve the desired pharmacodynamic profile in searching for new CNS-modulating agents.

The Phenoxyalkyltriazine Antagonists for 5-HT6 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-HT6 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-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor. Thus, a broader pharmacological profile for 1-3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT6 receptor target.