4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H3 Receptors and Cholinesterases.

This study examines the properties of a novel series of 4-oxypiperidines designed and synthesized as histamine H3R antagonists/inverse agonists based on the structural modification of two lead compounds, viz., ADS003 and ADS009. The products are intended to maintain a high affinity for H3R while simultaneously inhibiting AChE or/and BuChE enzymes. Selected compounds were subjected to hH3R radioligand displacement and gpH3R functional assays. Some of the compounds showed nanomolar affinity. The most promising compound in the naphthalene series was ADS031, which contained a benzyl moiety at position 1 of the piperidine ring and displayed 12.5 nM affinity at the hH3R and the highest inhibitory activity against AChE (IC50 = 1.537 µM). Eight compounds showed over 60% eqBuChE inhibition and hence were qualified for the determination of the IC50 value at eqBuChE; their values ranged from 0.559 to 2.655 µM. Therapy based on a multitarget-directed ligand combining H3R antagonism with additional AChE/BuChE inhibitory properties might improve cognitive functions in multifactorial Alzheimer's disease.

Chromium (III) removal by perennial emerging macrophytes in floating treatment wetlands.

Floating treatment wetlands (FTWs) are a sustainable solution to treat polluted water, but their role in chromium (Cr(III)) removal under neutral pH conditions remains poorly understood. This study evaluated the potential of FTWs planted with two perennial emergent macrophytes, Phragmites australis and Iris pseudacorus, to remove Cr(III) and nutrients (N and PO4-P) from water containing 7.5 mg/L TN, 1.8 mg/L PO4-P, and Cr(III) (500, 1000, and 2000 µg/L). Within 1 h of exposure, up to 96-99% of Cr was removed from the solution, indicating rapid precipitation. After 50 days, Phragmites bound 9-19% of added Cr, while Iris bound 5-22%. Both species accumulated Cr primarily in the roots (BCF > 1). Biomass production and growth development were inhibited in Cr treatments, but microscopic examination of plant roots revealed no histological changes at 500 and 1000 µg/L Cr, suggesting high resistance of the tested species. At 2000 µg/L Cr, both species exhibited disruptions in the arrangement of vessel elements in the stele and increased aerenchyma spaces in Phragmites. At the end of the experiment, 70-86% of TN and 54-90% of PO4-P were removed.

Efficacy of the Multi-Target Compound E153 in Relieving Pain and Pruritus of Different Origins.

Itch and pain are closely related but distinct sensations that share largely overlapping mediators and receptors. We hypothesized that the novel, multi-target compound E153 has the potential to attenuate pain and pruritus of different origins. After the evaluation of sigma receptor affinity and pharmacokinetic studies, we tested the compound using different procedures and models of pain and pruritus. Additionally, we used pharmacological tools, such as PRE-084, RAMH, JNJ 5207852, and S1RA, to precisely determine the role of histamine H3 and sigma 1 receptors in the analgesic and antipruritic effects of the compound. In vitro studies revealed that the test compound had potent affinity for sigma 1 and sigma 2 receptors, moderate affinity for opioid kappa receptors, and no affinity for delta or µ receptors. Pharmacokinetic studies showed that after intraperitoneal administration, the compound was present at high concentrations in both the peripheral tissues and the central nervous system. The blood-brain barrier-penetrating properties indicate its ability to act centrally at the levels of the brain and spinal cord. Furthermore, the test compound attenuated different types of pain, including acute, inflammatory, and neuropathic. It also showed a broad spectrum of antipruritic activity, attenuating histamine-dependent and histamine-independent itching. Finally, we proved that antagonism of both sigma 1 and histamine H3 receptors is involved in the analgesic activity of the compound, while the antipruritic effect to a greater extent depends on sigma 1 antagonism.

Novel object recognition test as an alternative approach to assessing the pharmacological profile of sigma-1 receptor ligands.

BACKGROUND: Although the terms "agonist" and "antagonist" have been used to classify sigma-1 receptor (σ1R) ligands, an unambiguous definition of the functional activity is often hard. In order to determine the pharmacological profile of σ1R ligands, the most common method is to assess their potency to alleviate opioid analgesia. It has been well established that σ1R agonists reduce opioid analgesic activity, while σ1R antagonists have been demonstrated to enhance opioid analgesia in different pain models. METHODS: In the present study, we evaluated the pharmacological profile of selected σ1R ligands using a novel object recognition (NOR) test, to see if any differences in cognitive functions between σ1R agonists and antagonists could be observed. We used the highly selective PRE-084 and S1RA as reference σ1R agonist and antagonist, respectively. Furthermore, compound KSK100 selected from our ligand library was also included in this study. KSK100 was previously characterized as a dual-targeting histamine H3/σ1R antagonist with antinociceptive and antiallodynic activity in vivo. Donepezil (acetylcholinesterase inhibitor and σ1R agonist) was used as a positive control drug. RESULTS: Both tested σ1R agonists (donepezil and PRE-084) improved learning in the NOR test, which was not observed with the σ1R antagonists S1RA and KSK100. CONCLUSIONS: The nonlinear dose-response effect of PRE-084 in this assay does not justify its use for routine assessment of the functional activity of σ1R ligands.

Multi-level Fgf4- and apoptosis-dependent regulatory mechanism ensures the plasticity of ESC-chimaeric mouse embryo.

The preimplantation mammalian (including mouse and human) embryo holds remarkable regulatory abilities, which have found their application, for example, in the preimplantation genetic diagnosis of human embryos. Another manifestation of this developmental plasticity is the possibility of obtaining chimaeras by combining either two embryos or embryos and pluripotent stem cells, which enables the verification of the cell pluripotency and generation of genetically modified animals used to elucidate gene function. Using mouse chimaeric embryos (constructed by injection of embryonic stem cells into the eight-cell embryos) as a tool, we aimed to explore the mechanisms underlying the regulatory nature of the preimplantation mouse embryo. We comprehensively demonstrated the functioning of a multi-level regulatory mechanism involving FGF4/MAPK signalling as a leading player in the communication between both components of the chimaera. This pathway, coupled with apoptosis, the cleavage division pattern and cell cycle duration controlling the size of the embryonic stem cell component and giving it a competitive advantage over host embryo blastomeres, provides a cellular and molecular basis for regulative development, ensuring the generation of the embryo characterised by proper cellular composition.

Dual Piperidine-Based Histamine H3 and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain.

In search of new dual-acting histamine H3/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active in vivo ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, KSK67 and KSK68, differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σ1Rs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds. In a series of 16 new ligands, mainly based on the piperidine core, we selected three lead structures (3, 7, and 12) for further biological evaluation. Compound 12 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models based on the novel molecular mechanism.

Structure-Activity Relationship and Solubility Studies of N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists.

Kainate receptors are a class of ionotropic glutamate receptors that respond to the excitatory neurotransmitter glutamate in the central nervous system and play an important role in the development of neurodegenerative disorders and the regulation of synaptic function. In the current study, we investigated the structure- activity relationship of the series of quinoxaline-2,3-diones substituted at N1, 6, and 7 positions, as ligands of kainate homomeric receptors GluK1-3 and GluK5. Pharmacological characterization showed that all derivatives obtained exhibited micromolar affinity at GluK3 receptors with Ki values in the range 0.1-4.4 µM range. The antagonistic properties of the selected analogues: N-(7-fluoro-6-iodo-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-3-sulfamoylbenzamide, N-(7-(1H-imidazol-1-yl)-6-iodo-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-3-sulfamoylbenzamide and N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(phenylethynyl)-3,4-dihydroquinoxalin-1(2H)-yl)-3-sulfamoylbenzamide at GluK3 receptors, were confirmed by an intracellular calcium imaging assay. To correlate in vitro affinity data with structural features of the synthesized compounds and to understand the impact of the substituent in N1 position on ability to form additional protein-ligand interactions, molecular modeling and docking studies were carried out. Experimental solubility studies using UV spectroscopy detection have shown that 7-imidazolyl-6-iodo analogues with a sulfamoylbenzamide moiety at the N1 position are the best soluble compounds in the series, with molar solubility in TRISS buffer at pH 9 more than 3-fold higher compared to NBQX, a known AMPA/kainate antagonist.

Evaluation of Some Safety Parameters of Dual Histamine H3 and Sigma-2 Receptor Ligands with Anti-Obesity Potential.

Many studies have shown the high efficacy of histamine H3 receptor ligands in preventing weight gain. In addition to evaluating the efficacy of future drug candidates, it is very important to assess their safety profile, which is established through numerous tests and preclinical studies. The purpose of the present study was to evaluate the safety of histamine H3/sigma-2 receptor ligands by assessing their effects on locomotor activity and motor coordination, as well as on the cardiac function, blood pressure, and plasma activity of certain cellular enzymes. The ligands tested at a dose of 10 mg/kg b.w. did not cause changes in locomotor activity (except for KSK-74) and did not affect motor coordination. Significant reductions in blood pressure were observed after the administration of compounds KSK-63, KSK-73, and KSK-74, which seems logically related to the increased effect of histamine. Although the results of in vitro studies suggest that the tested ligands can block the human ether-a-go-go-related gene (hERG) potassium channels, they did not affect cardiac parameters in vivo. It should be noted that repeated administration of the tested compounds prevented an increase in the activity of alanine aminotransferase (AlaT) and gamma-glutamyl transpeptidases (gGT) observed in the control animals fed a palatable diet. The obtained results show that the ligands selected for this research are not only effective in preventing weight gain but also demonstrate safety in relation to the evaluated parameters, allowing the compounds to proceed to the next stages of research.

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.

Cadmium accumulation by Phragmites australis and Iris pseudacorus from stormwater in floating treatment wetlands microcosms: Insights into plant tolerance and utility for phytoremediation.

Environmentally sustainable remediation is needed to protect freshwater resources which are deteriorating due to severe industrial, mining, and agricultural activities. Treatment by floating wetlands could be a sustainable solution to remediate water bodies. The study aimed to examine the effects of Cd on Phragmites australis and Iris pseudacorus growth (height, biomass, root length and chlorophyll contents), anatomy, Cd accumulation in their biomass and their ability to remove Cd, N and P. Seedlings of both plants were grown in a greenhouse for 50 days in artificially prepared stormwater amended with Cd, N, and P. The treatments were: control (Cd _0), Cd_1, Cd_2, and Cd_4 mg L-1. N and P contents were 4 mg L-1 and 1.8 mg L-1, respectively. In the case of P. australis, the maximum plant height, root length, and total dry biomass production was increased in medium dose (Cd_2) treatment while the chlorophyll index (CCI) increased in high dose (Cd_4) treatment as compared to all treatments. For I. pseudacorus, the maximum plant height and total dry biomass production, root length and CCI values were improved in low dose (Cd_1) and high dose (Cd_4) treatments, respectively among all treatments. Results showed that P. australis accumulated 10.94-1821.59 µg · (0.05 m2)-1 in roots and 2.45-334.65 µg · (0.05 m2)-1 in shoots under Cd_0, Cd_1 and Cd_4 treatments. I. pseudacorus accumulated the highest Cd in roots up to 5.84-4900 µg · (0.05 m2)-1 and 3.40-609 µg · (0.05 m2)-1 in shoots under Cd_0, Cd_1 and Cd_4 treatments. The translocation factor was observed as <1 and the bioconcentration factor >1 for both species, which indicates their phytostabilization potential. Results demonstrate that P. australis and I. pseudacorus are suitable for use in floating wetlands to remediate contaminated sites.

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.

Paracrine interactions through FGFR1 and FGFR2 receptors regulate the development of preimplantation mouse chimaeric embryo.

The preimplantation mammalian embryo has the potential to self-organize, allowing the formation of a correctly patterned embryo despite experimental perturbation. To better understand the mechanisms controlling the developmental plasticity of the early mouse embryo, we used chimaeras composed of an embryonic day (E)3.5 or E4.5 inner cell mass (ICM) and cleaving 8-cell embryo. We revealed that the restricted potential of the ICM can be compensated for by uncommitted 8-cell embryo-derived blastomeres, thus leading to the formation of a normal chimaeric blastocyst that can undergo full development. However, whether such chimaeras maintain developmental competence depends on the presence or specific orientation of the polarized primitive endoderm layer in the ICM component. We also demonstrated that downregulated FGFR1 and FGFR2 expression in 8-cell embryos disturbs intercellular interactions between both components and results in an inverse proportion of primitive endoderm and epiblast within the resulting ICM and abnormal embryo development. This finding suggests that FGF signalling is a key part of the regulatory mechanism that assigns cells to a given lineage and ensures the proper composition of the blastocyst, which is a prerequisite for its successful implantation in the uterus and for further development.

KSK-74: Dual Histamine H3 and Sigma-2 Receptor Ligand with Anti-Obesity Potential.

Many studies involving compounds that enhance histamine release, such as histamine H3 receptor (H3R) antagonists, have shown efficacy in inhibiting weight gain, but none have passed clinical trials. As part of the search for H3 receptor ligands that have additional properties, the aim of this study is to evaluate the activity in the reduction in weight gain in a rat model of excessive eating, as well as the impact on selected metabolic parameters, and the number and size of adipocytes of two new H3R antagonists, KSK-60 and KSK-74, which also exert a significant affinity at the sigma-2 receptor. Compounds KSK-60 and KSK-74 are homologues and the elongation of the distal part of the molecule resulted in an approximate two-fold reduction in affinity at H3R, but simultaneously an almost two-fold increase in affinity at the sigma-2 receptor. Animals fed palatable feed and receiving KSK-60 or KSK-74 both at 10 mg/kg b.w. gained significantly less weight than animals in the control obese group. Moreover, KSK-74 significantly compensated for metabolic disturbances that accompany obesity, such as an increase in plasma triglyceride, resistin, and leptin levels; improved glucose tolerance; and protected experimental animals against adipocyte hypertrophy. Furthermore, KSK-74 inhibited the development of inflammation in obesity-exposed adipose tissue. The in vivo pharmacological activity of the tested ligands appears to correlate with the affinity at the sigma-2 receptors; however, the explanation of this phenomenon requires further and extended research.

Burden and severity of disease of aromatic L-amino acid decarboxylase deficiency: a systematic literature review.

OBJECTIVE: The objective was to investigate the severity of aromatic L-amino acid decarboxylase deficiency (AADCd) as reported in the published literature and to collate evidence of the clinical manifestations of AADCd, and the impact of the disease on patients, caregivers, and healthcare systems. METHODS: Published articles reporting severity of disease or disease impact were eligible for inclusion in this review. Articles were searched in MEDLINE, EMBASE, Cochrane CENTRAL, TRIP medical, and CRD databases in October 2021. The quality of the included studies was investigated using a modified version of the grading system of the Centre for Evidence-Based Medicine (CEBM). Descriptive data of the literature was extracted and a narrative synthesis of the results across studies was conducted. This review is reported according to the PRISMA reporting guidelines for systematic reviews. RESULTS: The search identified 970 unique reports, of which 59 met eligibility criteria to be included in the review. Of these, 48 included reports provided details on the clinical manifestations of AADCd. Two reports explored the disease impact on patients, while four described the impact on caregivers. Five reports assessed the impact on healthcare systems. Individuals with AADCd experience very severe clinical manifestations regardless of motor milestones achieved, and present with a spectrum of other complications. Individuals with AADCd present with very limited function, which, in combination with additional complications, substantially impact the quality-of-life of individuals and their caregivers. The five studies which explore the impact on the healthcare system reported that adequate care of individuals with AADCd requires a vast array of medical services and supportive therapies. CONCLUSIONS: Irrespective of the ambulatory status of individuals, AADCd is a debilitating disease that significantly impacts quality-of-life for individuals and caregivers. It impacts the healthcare system due to the need for complex coordinated activities of a multidisciplinary specialist team.

Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H3 and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties.

In an attempt to extend recent studies showing that some clinically evaluated histamine H3 receptor (H3R) antagonists possess nanomolar affinity at sigma-1 receptors (σ1R), we selected 20 representative structures among our previously reported H3R ligands to investigate their affinity at σRs. Most of the tested compounds interact with both sigma receptors to different degrees. However, only six of them showed higher affinity toward σ1R than σ2R with the highest binding preference to σ1R for compounds 5, 11, and 12. Moreover, all these ligands share a common structural feature: the piperidine moiety as the fundamental part of the molecule. It is most likely a critical structural element for dual H3/σ1 receptor activity as can be seen by comparing the data for compounds 4 and 5 (hH3R Ki = 3.17 and 7.70 nM, σ1R Ki = 1531 and 3.64 nM, respectively), where piperidine is replaced by piperazine. We identified the putative protein-ligand interactions responsible for their high affinity using molecular modeling techniques and selected compounds 5 and 11 as lead structures for further evaluation. Interestingly, both ligands turned out to be high-affinity histamine H3 and σ1 receptor antagonists with negligible affinity at the other histamine receptor subtypes and promising antinociceptive activity in vivo. Considering that many literature data clearly indicate high preclinical efficacy of individual selective σ1 or H3R ligands in various pain models, our research might be a breakthrough in the search for novel, dual-acting compounds that can improve existing pain therapies. Determining whether such ligands are more effective than single-selective drugs will be the subject of our future studies.

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.

Metabolic benefits of novel histamine H3 receptor ligands in the model of excessive eating: The importance of intrinsic activity and pharmacokinetic properties.

AIMS: One of the therapeutic approaches in the treatment of obesity is the use of histamine H3 receptor ligands. Histamine plays a significant role in eating behavior because it causes a loss of appetite and is considered to be a satiety signal released during food intake. MATERIAL AND METHODS: Histamine ligands were selected based on the preliminary studies which included determination of intrinsic activity and selected pharmacokinetic parameters. Female Wistar rats were fed palatable feed for 28 days and simultaneously the tested compounds were administered intraperitoneally at a dose of 10 mg/kg b.w./day. Rats' weight was evaluated daily and calories intake was evaluated once per week. At the end of experiment insulin and glucose tolerance tests was performed. Plasma levels of cholesterol, triglycerides, leptin, insulin, glucose, C-peptide and CRP were also determined. In order to rule out false-positive results the influence of tested compounds on spontaneous activity of rats was monitored. RESULTS: Animals fed palatable feed and treated with KSK-61 or KSK-63 compounds showed the slowest weight gain which was comparable to the one observed in control animals. Both compounds with the highest pharmacological activity have also similar pharmacokinetic properties with quite long half-life and high volume of distribution indicating that they can freely cross most biological barriers. Some compounds, especially KSK-63, compensated for metabolic disorders. CONCLUSION: The presented study proves that search among the active histamine H3 receptor ligands for the new therapeutic agents to treat obesity is justified. Compounds KSK-61 and KSK-63 can be considered as the leading structures.

Discovery of Potential, Dual-Active Histamine H3 Receptor Ligands with Combined Antioxidant Properties.

In an attempt to find new dual acting histamine H3 receptor (H3R) ligands, we designed a series of compounds, structurally based on previously described in our group, a highly active and selective human histamine H3 receptor (hH3R) ligand KSK63. As a result, 15 obtained compounds show moderate hH3R affinity, the best being the compound 17 (hH3R Ki = 518 nM). Docking to the histamine H3R homology model revealed two possible binding modes, with key interactions retained in both cases. In an attempt to find possible dual acting ligands, selected compounds were tested for antioxidant properties. Compound 16 (hH3R Ki = 592 nM) showed the strongest antioxidant properties at the concentration of 10-4 mol/L. It significantly reduced the amount of free radicals presenting 50-60% of ascorbic acid activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, as well as showed antioxidative properties in the ferric reducing antioxidant power (FRAP) assay. Despite the yet unknown antioxidation mechanism and moderate hH3R affinity, 16 (QD13) constitutes a starting point for the search of potential dual acting H3R ligands-promising tools for the treatment of neurological disorders associated with increased neuronal oxidative stress.

Infraspecific variation of some brown Parmeliae (in Poland) - a comparison of ITS rDNA and non-molecular characters.

Infraspecific variation of the ITS rDNA region of some brown Parmeliae occurring in Poland is studied and compared with non-molecular characters. Haplotype networks are used to illustrate the variability within the species. Both newly-produced sequences from Central Europe and from all over the world, downloaded from the GenBank, are used. The number of haplotypes found for each taxon ranged from five in Melaneliastygia to 12 in Melaneliahepatizon and Montaneliadisjuncta; however, their numbers correlate with the number of specimens tested. New haplotypes for Melaneliaagnata, M.hepatizon and Cetrariacommixta are found. Based on our 169-sample dataset, we could not infer any geographical correlation, either locally or world-wide. Many of the analysed haplotypes were widely distributed and the same haplotype was often shared between temperate and polar populations. A comparison of molecular, morphological, anatomical and chemical characters also shows no correlation.

Structural modifications in the distal, regulatory region of histamine H3 receptor antagonists leading to the identification of a potent anti-obesity agent.

A series of 4-pyridylpiperazine derivatives with varying regulatory region substituents proved to be potent histamine H3 receptor (H3R) ligands in the nanomolar concentration range. The most influential modification that affected the affinity toward the H3R appeared by introducing electron-withdrawing moieties into the distal aromatic ring. In order to finally discuss the influence of the characteristic 4-pyridylpiperazine moiety on H3R affinity, two Ciproxifan analogues 2 and 3 with a slight modification in their basic part were obtained. The replacement of piperazine in 3 with piperidine in compound 2, led to slightly reduced affinity towards the H3R (Ki = 3.17 and 7.70 nM, respectively). In fact, 3 showed the highest antagonistic properties among all compounds in this series, hence affirming our previous assumptions, that the 4-pyridylpiperazine moiety is the key element for suitable interaction with the human histamine H3 receptor. While its structural replacement to piperidine is also tolerated for H3R binding, the heteroaromatic 4-pyridyl moiety seems to be essential for proper ligand-receptor interaction. The putative protein-ligand interactions responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at the H3R, as well as drug-like properties of ligands were evaluated using in vitro methods. Moreover, pharmacological in vivo test results of compound 9 (structural analogue of Abbott's A-331440) clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound.