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.     

A Molecular and Chemical Perspective in Defining Melatonin Receptor Subtype Selectivity

Melatonin is primarily synthesized and secreted by the pineal gland during darkness in a normal diurnal cycle. In addition to its intrinsic antioxidant property, the neurohormone has renowned regulatory roles in the control of circadian rhythm and exerts its physiological actions primarily by interacting with the G protein-coupled MT₁ and MT₂ transmembrane receptors. The two melatonin receptor subtypes display identical ligand binding characteristics and mediate a myriad of signaling pathways, including adenylyl cyclase inhibition, phospholipase C stimulation and the regulation of other effector molecules. Both MT₁ and MT₂ receptors are widely expressed in the central nervous system as well as many peripheral tissues, but each receptor subtype can be linked to specific functional responses at the target tissue. Given the broad therapeutic implications of melatonin receptors in chronobiology, immunomodulation, endocrine regulation, reproductive functions and cancer development, drug discovery and development programs have been directed at identifying chemical molecules that bind to the two melatonin receptor subtypes. However, all of the melatoninergics in the market act on both subtypes of melatonin receptors without significant selectivity. To facilitate the design and development of novel therapeutic agents, it is necessary to understand the intrinsic differences between MT₁ and MT₂ that determine ligand binding, functional efficacy, and signaling specificity. This review summarizes our current knowledge in differentiating MT₁ and MT₂ receptors and their signaling capacities. The use of homology modeling in the mapping of the ligand-binding pocket will be described. Identification of conserved and distinct residues will be tremendously useful in the design of highly selective ligands.     

Involvement of Histamine H3 Receptor Agonism in Premature Ejaculation Found by Studies in Rats

Several of the drugs currently available for the treatment of premature ejaculation (PE) (e.g., local anesthetics or antidepressants) are associated with numerous safety concerns and exhibit weak efficacy. To date, no therapeutics for PE have been approved in the United States, highlighting the need to develop novel agents with sufficient efficacy and fewer side effects. In this study, we focused on the histamine H₃ receptor (H₃R) as a potential target for the treatment of PE and evaluated the effects of imetit (an H₃R/H₄R agonist), ciproxifan (an H₃R antagonist), and JNJ-7777120 (an H₄R antagonist) in vivo. Our in vivo electrophysiological experiments revealed that imetit reduced mechanical stimuli-evoked neuronal firing in anesthetized rats. This effect was inhibited by ciproxifan but not by JNJ-7777120. Subsequently, we evaluated the effect of imetit using a copulatory behavior test to assess ejaculation latency (EL) in rats. Imetit prolonged EL, although this effect was inhibited by ciproxifan. These findings indicate that H₃R stimulation suppresses mechanical stimuli-evoked neuronal firing in the spinal–penile neurotransmission system, thereby resulting in prolonged EL. To our knowledge, this is the first report to describe the relationship between H₃R and PE. Thus, H₃R agonists may represent a novel treatment option for PE.     

Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D3-Selective Antagonists

Previous studies have confirmed that the binding of D₃ receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D₃ receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D₃ receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D₃ receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D₃ receptor affinities (Ki = 0.8–13.2 nM) with subtype selectivity to the D₂ receptor ranging from 22- to 180-fold. The β-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC₅₀ = 1.3 nM). Computational studies demonstrated that the high potency of 21c and its analogs was the result of interactions with the secondary binding site of the D₃ receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT₃ receptors and TSPO. The results of this study revealed that a new class of selective D₃ receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.     

Synthesis, structure, and photovoltaic property of a nanocrystalline 2H perovskite-type novel sensitizer (CH3CH2NH3)PbI3

A new nanocrystalline sensitizer with the chemical formula (CH₃CH₂NH₃)PbI₃ is synthesized by reacting ethylammonium iodide with lead iodide, and its crystal structure and photovoltaic property are investigated. X-ray diffraction analysis confirms orthorhombic crystal phase with a = 8.7419(2) Å, b = 8.14745(10) Å, and c = 30.3096(6) Å, which can be described as 2 H perovskite structure. Ultraviolet photoelectron spectroscopy and UV-visible spectroscopy determine the valence band position at 5.6 eV versus vacuum and the optical bandgap of ca. 2.2 eV. A spin coating of the CH₃CH₂NH₃I and PbI₂ mixed solution on a TiO₂ film yields ca. 1.8-nm-diameter (CH₃CH₂NH₃)PbI₃ dots on the TiO₂ surface. The (CH₃CH₂NH₃)PbI₃-sensitized solar cell with iodide-based redox electrolyte demonstrates the conversion efficiency of 2.4% under AM 1.5 G one sun (100 mW/cm²) illumination.     

Synthesis and photocatalytic properties of H2La2Ti3O10/TiO2 intercalated nanomaterial

H₂La₂Ti₃O₁₀/ TiO₂ intercalated nanomaterial was fabricated by successive intercalation reactions of H₂La₂Ti₃O₁₀ with n-C₆H₁₃NH₂/C₂H₅OH mixed solution and acid TiO₂ sol, followed by irradiating with a high-pressure mercury lamp. The intercalated materials possess a gallery height of 0.46 nm and a specific surface area of 31.58 m²·g⁻¹, which indicate the formation of a porous material. H₂La₂Ti₃O₁₀/TiO₂ shows photocatalytic activity for the decomposition of organic dye under irradiation with visible light and the activity of TiO₂ intercalated material was superior to the unsupported one.     

Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E4106.30×30K Variant in the Histamine H1 Receptor

The Exome Aggregation Consortium has collected the protein-encoding DNA sequences of almost 61,000 unrelated humans. Analysis of this dataset for G protein-coupled receptor (GPCR) proteins (available at GPCRdb) revealed a total of 463 naturally occurring genetic missense variations in the histamine receptor family. In this research, we have analyzed the distribution of these missense variations in the four histamine receptor subtypes concerning structural segments and sites important for GPCR function. Four missense variants R127^3.52×52H, R139^34.57×57H, R409^6.29×29H, and E410^6.30×30K, were selected for the histamine H₁ receptor (H₁R) that were hypothesized to affect receptor activity by interfering with the interaction pattern of the highly conserved D(E)RY motif, the so-called ionic lock. The E410^6.30×30K missense variant displays higher constitutive activity in G protein signaling as compared to wild-type H₁R, whereas the opposite was observed for R127^3.52×52H, R139^34.57×57H, and R409^6.29×29H. The E410^6.30×30K missense variant displays a higher affinity for the endogenous agonist histamine than wild-type H₁R, whereas antagonist affinity was not affected. These data support the hypothesis that the E410^6.30×30K mutation shifts the equilibrium towards active conformations. The study of these selected missense variants gives additional insight into the structural basis of H₁R activation and, moreover, highlights that missense variants can result in pharmacologically different behavior as compared to wild-type receptors and should consequently be considered in the drug discovery process.     

Synthesis and Characterization of Some New Bis-Pyrazolyl-Thiazoles Incorporating the Thiophene Moiety as Potent Anti-Tumor Agents

A new series of 1,4-bis(1-(5-(aryldiazenyl)thiazol-2-yl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-3-yl)benzenes 3a–i were synthesized via reaction of 5,5′-(1,4-phenylene)bis(3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide) (1) with hydrazonoyl halides 2a–i. In addition, reaction of 1 with ethyl chloroacetate afforded bis-thiazolone derivative 8 as the end product. Reaction of compound 8 with methyl glyoxalate gave bis-thiazolone derivative 10. The structures of the newly synthesized compounds were established on the basis of spectroscopic evidences and their alternative syntheses. All the synthesized compounds were evaluated for their anti-tumor activities against hepatocellular carcinoma (HepG2) cell lines, and the results revealed promising activities of compounds 3g, 5e, 3e, 10, 5f, 3i, and 3f with IC₅₀ equal 1.37 ± 0.15, 1.41 ± 0.17, 1.62 ± 0.20, 1.86 ± 0.20, 1.93 ± 0.08, 2.03 ± 0.25, and 2.09 ± 0.19 μM, respectively.     

Synthesis and Characterization of Bowl-Like Single-Crystalline BaTiO3 Nanoparticles

Novel bowl-like single-crystalline BaTiO₃ nanoparticles were synthesized by a simple hydrothermal method using Ba(OH)₂·8H₂O and TiO₂ as precursors. The as-prepared products were characterized by XRD, Raman spectroscopy, SEM and TEM. The results show that the bowl-like BaTiO₃ nanoparticles are single-crystalline and have a size about 100–200 nm in diameter. Local piezoresponse force measurements indicate that the BaTiO₃ nanoparticles have switchable polarization at room temperature. The local effective piezoelectric coefficient d₃₃ ^* d_{33}^{ * } is approximately 28 pm/V.     

Differential Regulation of Bilastine Affinity for Human Histamine H1 Receptors by Lys 179 and Lys 191 via Its Binding Enthalpy and Entropy

Bilastine, a zwitterionic second-generation antihistamine containing a carboxyl group, has higher selectivity for H₁ receptors than first-generation antihistamines. Ligand-receptor docking simulations have suggested that the electrostatic interaction between the carboxyl group of second-generation antihistamines and the amino group of Lys179^ECL2 and Lys191^5.39 of human H₁ receptors might contribute to increased affinity of these antihistamines to H₁ receptors. In this study, we evaluated the roles of Lys179^ECL2 and Lys191^5.39 in regulating the electrostatic and hydrophobic binding of bilastine to H₁ receptors by thermodynamic analyses. The binding enthalpy and entropy of bilastine were estimated from the van ’t Hoff equation using the dissociation constants. These constants were obtained from the displacement curves against the binding of [³H] mepyramine to membrane preparations of Chinese hamster ovary cells expressing wild-type human H₁ receptors and their Lys179^ECL2 or Lys191^5.39 mutants to alanine at various temperatures. We found that the binding of bilastine to wild-type H₁ receptors occurred by enthalpy-dependent binding forces and, more dominantly, entropy-dependent binding forces. The mutation of Lys179^ECL2 and Lys191^5.39 to alanine reduced the affinity of bilastine to H₁ receptors by reducing enthalpy- and entropy-dependent binding forces, respectively. These results suggest that Lys179^ECL2 and Lys191^5.39 differentially contribute to the increased binding affinity to bilastine via electrostatic and hydrophobic binding forces.     

Computational Analysis of Structure-Based Interactions for Novel H1-Antihistamines

As a chronic disorder, insomnia affects approximately 10% of the population at some time during their lives, and its treatment is often challenging. Since the antagonists of the H₁ receptor, a protein prevalent in human central nervous system, have been proven as effective therapeutic agents for treating insomnia, the H₁ receptor is quite possibly a promising target for developing potent anti-insomnia drugs. For the purpose of understanding the structural actors affecting the antagonism potency, presently a theoretical research of molecular interactions between 129 molecules and the H₁ receptor is performed through three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. The ligand-based comparative molecular similarity indices analysis (CoMSIA) model (Q² = 0.525, R²_ncv = 0.891, R²_pred = 0.807) has good quality for predicting the bioactivities of new chemicals. The cross-validated result suggests that the developed models have excellent internal and external predictability and consistency. The obtained contour maps were appraised for affinity trends for the investigated compounds, which provides significantly useful information in the rational drug design of novel anti-insomnia agents. Molecular docking was also performed to investigate the mode of interaction between the ligand and the active site of the receptor. Furthermore, as a supplementary tool to study the docking conformation of the antagonists in the H₁ receptor binding pocket, molecular dynamics simulation was also applied, providing insights into the changes in the structure. All of the models and the derived information would, we hope, be of help for developing novel potent histamine H₁ receptor antagonists, as well as exploring the H₁-antihistamines interaction mechanism.     

Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations

G protein-coupled receptors (GPCRs) are targets of extracellular stimuli and hence occupy a key position in drug discovery. By specific and not yet fully elucidated coupling profiles with α subunits of distinct G protein families, they regulate cellular responses. The histamine H₂ and H₄ receptors (H₂R and H₄R) are prominent members of Gs- and Gi-coupled GPCRs. Nevertheless, promiscuous G protein and selective Gi signaling have been reported for the H₂R and H₄R, respectively, the molecular mechanism of which remained unclear. Using a combination of cellular experimental assays and Gaussian accelerated molecular dynamics (GaMD) simulations, we investigated the coupling profiles of the H₂R and H₄R to engineered mini-G proteins (mG). We obtained coupling profiles of the mGs, mGsi, or mGsq proteins to the H₂R and H₄R from the mini-G protein recruitment assays using HEK293T cells. Compared to H₂R–mGs expressing cells, histamine responses were weaker (pEC₅₀, E_max) for H₂R–mGsi and –mGsq. By contrast, the H₄R selectively bound to mGsi. Similarly, in all-atom GaMD simulations, we observed a preferential binding of H₂R to mGs and H₄R to mGsi revealed by the structural flexibility and free energy landscapes of the complexes. Although the mG α5 helices were consistently located within the HR binding cavity, alternative binding orientations were detected in the complexes. Due to the specific residue interactions, all mG α5 helices of the H₂R complexes adopted the Gs-like orientation toward the receptor transmembrane (TM) 6 domain, whereas in H₄R complexes, only mGsi was in the Gi-like orientation toward TM2, which was in agreement with Gs- and Gi-coupled GPCRs structures resolved by X-ray/cryo-EM. These cellular and molecular insights support (patho)physiological profiles of the histamine receptors, especially the hitherto little studied H₂R function in the brain, as well as of the pharmacological potential of H₄R selective drugs.     

Cobalt Alleviates GA-Induced Programmed Cell Death in Wheat Aleurone Layers via the Regulation of H2O2 Production and Heme Oxygenase-1 Expression

Heme oxygenase-1 (HO-1) and hydrogen peroxide (H₂O₂) are key signaling molecules that are produced in response to various environmental stimuli. Here, we demonstrate that cobalt is able to delay gibberellic acid (GA)-induced programmed cell death (PCD) in wheat aleurone layers. A similar response was observed when samples were pretreated with carbon monoxide (CO) or bilirubin (BR), two end-products of HO catalysis. We further observed that increased HO-1 expression played a role in the cobalt-induced alleviation of PCD. The application of HO-1-specific inhibitor, zinc protoporphyrin-IX (ZnPPIX), substantially prevented the increases of HO-1 activity and the alleviation of PCD triggered by cobalt. The stimulation of HO-1 expression, and alleviation of PCD might be caused by the initial H₂O₂ production induced by cobalt. qRT-PCR and enzymatic assays revealed that cobalt-induced gene expression and the corresponding activities of superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX), three enzymes that metabolize reactive oxygen species, were consistent with the H₂O₂ accumulation during GA treatment. These cobalt responses were differentially blocked by co-treatment with ZnPPIX. We therefore suggest that HO-1 functions in the cobalt-triggered alleviation of PCD in wheat aleurone layers, which is also dependent on the enhancement of the activities of antioxidant enzymes.     

Characterization of photovoltaics with In2S3 nanoflakes/p-Si heterojunction

We demonstrate that heterojunction photovoltaics based on hydrothermal-grown In₂S₃ on p-Si were fabricated and characterized in the paper. An n-type In₂S₃ nanoflake-based film with unique ''cross-linked network’ structure was grown on the prepared p-type silicon substrate. It was found that the bandgap energy of such In₂S₃ film is 2.5 eV by optical absorption spectra. This unique nanostructure significantly enhances the surface area of the In₂S₃ films, leading to obtain lower reflectance spectra as the thickness of In₂S₃ film was increased. Additionally, such a nanostructure resulted in a closer spacing between the cross-linked In₂S₃ nanostructures and formed more direct conduction paths for electron transportation. Thus, the short-circuit current density (Jsc) was effectively improved by using a suitable thickness of In₂S₃. The power conversion efficiency (PCE, η) of the AZO/In₂S₃/textured p-Si heterojunction solar cell with 100-nm-thick In₂S₃ film was 2.39%.     

A Convenient Synthesis of Some Coumarin Derivatives Using SnCl2 · 2H2O as Catalyst

Some substituted coumarins have been synthesized by von-Pechmann condensation using SnCl₂ · 2H₂O (10 mol %) as catalyst in ethanolic medium. The reactions are simple, easy in handling and environmentally benign.     

Melamine-(H2SO4)3/melamine-(HNO3)3 instead of H2SO4/HNO3: a safe system for the fast oxidation of thiols and sulfides under solvent-free conditions

Melamine reacted with neat sulfuric acid and fuming nitric acid readily to form two new organic solid acids, namely melamine-(H₂SO₄)₃ and melamine-(HNO₃)₃. Mixture of them acts as a unique powerful system instead of a hazardous H₂SO₄/HNO₃ system for the direct oxidation of thiols. Also, this system can oxidize the sulfides in the presence of a catalytic amount of KBr and few drops of water. This procedure offers advantages such as very low reaction time, simple work-up, excellent yield and matching with some green chemistry protocols.     

Use of a Reflectance Spectroscopy Accessory for Optical Characterization of ZnO-Bi(2)O(3)-TiO(2) Ceramics

The optical band-gap energy (E(g)) is an important feature of semiconductors which determines their applications in optoelectronics. Therefore, it is necessary to investigate the electronic states of ceramic ZnO and the effect of doped impurities under different processing conditions. E(g) of the ceramic ZnO + xBi(2)O(3) + xTiO(2), where x = 0.5 mol%, was determined using a UV-Vis spectrophotometer attached to a Reflectance Spectroscopy Accessory for powdered samples. The samples was prepared using the solid-state route and sintered at temperatures from 1140 to 1260 °C for 45 and 90 minutes. E(g) was observed to decrease with an increase of sintering temperature. XRD analysis indicated hexagonal ZnO and few small peaks of intergranular layers of secondary phases. The relative density of the sintered ceramics decreased and the average grain size increased with the increase of sintering temperature.     

Side-by-Side In(OH)<Subscript>3</Subscript> and In<Subscript>2</Subscript>O<Subscript>3</Subscript> Nanotubes: Synthesis and Optical Properties

A simple and mild wet-chemical approach was developed for the synthesis of one-dimensional (1D) In(OH)₃ nanostructures. By calcining the 1D In(OH)₃ nanocrystals in air at 250 °C, 1D In₂O₃ nanocrystals with the same morphology were obtained. TEM results show that both 1D In(OH)₃ and 1D In₂O₃ are composed of uniform nanotube bundles. SAED and XRD patterns indicate that 1D In(OH)₃ and 1D In₂O₃ nanostructures are single crystalline and possess the same bcc crystalline structure as the bulk In(OH)₃ and In₂O₃, respectively. TGA/DTA analyses of the precursor In(OH)₃ and the final product In₂O₃ confirm the existence of CTAB molecules, and its content is about 6%. The optical absorption band edge of 1D In₂O₃ exhibits an evident blueshift with respect to that of the commercial In₂O₃ powders, which is caused by the increasing energy gap resulted from decreasing the grain size. A relatively strong and broad purple-blue emission band centered at 440 nm was observed in the room temperature PL spectrum of 1D In₂O₃ nanotube bundles, which was mainly attributed to the existence of the oxygen vacancies.     

Nanocasting Synthesis of Ultrafine WO<Subscript>3</Subscript> Nanoparticles for Gas Sensing Applications

Ultrafine WO₃ nanoparticles were synthesized by nanocasting route, using mesoporous SiO₂ as a template. BET measurements showed a specific surface area of 700 m²/gr for synthesized SiO_2, while after impregnation and template removal, this area was reduced to 43 m²/gr for WO3 nanoparticles. HRTEM results showed single crystalline nanoparticles with average particle size of about 5 nm possessing a monoclinic structure, which is the favorite crystal structure for gas sensing applications. Gas sensor was fabricated by deposition of WO₃ nanoparticles between electrodes via low frequency AC electrophoretic deposition. Gas sensing measurements showed that this material has a high sensitivity to very low concentrations of NO₂ at 250°C and 300°C.