scholarly journals Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4472 ◽  
Author(s):  
Annamaria Lubelska ◽  
Gniewomir Latacz ◽  
Magdalena Jastrzębska-Więsek ◽  
Magdalena Kotańska ◽  
Rafał Kurczab ◽  
...  
Keyword(s):  
Serotonin Receptor ◽  
Chemical Space ◽  
Active Member ◽  
Biochemical Tests ◽  
Behavioral Studies ◽  
Plus Maze ◽  
Pharmacological Studies ◽  
Cns Drugs

Though the 5-HT6 serotonin receptor is an important target giving both agonists and antagonists similar therapeutic potency in the treatment of topic CNS-diseases, no 5-HT6R ligand has reached the pharmaceutical market yet due to the too narrow chemical space of the known 5-HT6R agents and insufficient “drugability.” Recently, a new group of non-indole and non-sulfone hydantoin-triazine 5-HT6R ligands was found, where 3-((4-amino-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-yl)methyl)-5-methyl-5-(naphthalen-2-yl)imidazolidine-2,4-dione (KMP-10) was the most active member. This study is focused on wider pharmacological and “druglikeness” characteristics for KMP-10. A computer-aided insight into molecular interactions with 5-HT6R has been performed. “Druglikeness” was examined using an eight-test panel in vitro, i.e., a parallel artificial membrane permeability assay (PAMPA), and Caco-2 permeability-, P-glycoprotein (Pgp) affinity-, plasma protein binding-, metabolic stability- and drug–drug interaction-assays, as well as mutagenicity- and HepG2-hepatotoxicity risk tests. Behavioral studies in vivo, i.e., elevated plus-maze (EPM) and novel object recognition (NOR) tests, were performed. Extended studies on the influence of KMP-10 on rats’ metabolism, including biochemical tests, were conducted in vivo. Results indicated significant anxiolytic and precognitive properties, as well as some anti-obesity properties in vivo, and it was found to satisfy the “druglikeness” profile in vitro for KMP-10. The compound seems to be a good lead-structure and candidate for wider pharmacological studies in search for new CNS-drugs acting via 5-HT6R.

scholarly journals The 1,3,5-Triazine Derivatives as Innovative Chemical Family of 5-HT6 Serotonin Receptor Agents with Therapeutic Perspectives for Cognitive Impairment

2019 ◽  
Vol 20 (14) ◽  
pp. 3420 ◽  
Author(s):  
Gniewomir Latacz ◽  
Annamaria Lubelska ◽  
Magdalena Jastrzębska-Więsek ◽  
Anna Partyka ◽  
Małgorzata Anna Marć ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Serotonin Receptors ◽  
Serotonin Receptor ◽  
Molecular Mechanisms ◽  
Binding Properties ◽  
Piperazine Derivatives ◽  
Behavioral Studies ◽  
Triazine Derivatives

Among serotonin receptors, the 5-HT6 subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HT6R ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient “druglikeness” properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family of potent 5-HT6R ligands. For the most active triazine 5-HT6R agents found (1–4), a wider binding profile and comprehensive in vitro evaluation of their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were investigated within this work. Results indicated the most promising pharmacological/druglikeness profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) and 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (4), which displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative (4) seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and non-sulfone structure with the best 5-HT6R binding properties.

Ferula hermonis: A Review of Current Use and Pharmacological Studies of its Sesquiterpene Ester Ferutinin

2020 ◽  
Vol 21 (5) ◽  
pp. 499-508 ◽  
Author(s):  
Rémi Safi ◽  
Marwan El-Sabban ◽  
Fadia Najjar
Keyword(s):  
Wide Spectrum ◽  
Endemic Plant ◽  
Anti Cancer ◽  
Pharmacological Studies ◽  
Sexual Impotence ◽  
Novel Applications ◽  
Anti Fungal ◽  
Sesquiterpene Ester

Ferula hermonis Boiss, is an endemic plant of Lebanon, locally known as “shilsh Elzallouh”. It has been extensively used in the traditional medicine as an aphrodisiac and for the treatment of sexual impotence. Crude extracts and isolated compounds of ferula hermonis contain phytoestrogenic substances having a wide spectrum of in vitro and in vivo pharmacological properties including anti-osteoporosis, anti-inflammatory, anti-microbial and anti-fungal, anti-cancer and as sexual activity enhancer. The aim of this mini-review is to highlight the traditional and novel applications of this plant’s extracts and its major sesquiterpene ester, ferutinin. The phytochemical constituents and the pharmacological uses of ferula hermonis crude extract and ferutinin specifically will be discussed.

scholarly journals The Genus Lagochilus (Lamiaceae): A Review of Its Diversity, Ethnobotany, Phytochemistry, and Pharmacology

Plants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 132
Author(s):  
Nilufar Z. Mamadalieva ◽  
Davlat Kh. Akramov ◽  
Ludger A. Wessjohann ◽  
Hidayat Hussain ◽  
Chunlin Long ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Chemical Constituents ◽  
Iridoid Glycosides ◽  
Herbal Medicines ◽  
Future Research ◽  
South Central ◽  
Pharmacological Studies ◽  
Central South

The genus Lagochilus (Lamiaceae) is native to Central, South-Central, and Eastern Asia. It comprises 44 species, which have been commonly used as herbal medicines for the treatments of various ailments for thousands of years, especially in Asian countries. This review aims to summarize the chemical constituents and pharmacological activities of species from the genus Lagochilus to unveil opportunities for future research. In addition, we provide some information about their traditional uses, botany, and diversity. More than 150 secondary metabolites have been reported from Lagochilus, including diterpenes, flavonoids, phenolic compounds, triterpenoids, iridoid glycosides, lignans, steroids, alkaloids, polysaccharides, volatile, non-volatile and aromatic compounds, lipids, carbohydrates, minerals, vitamins, and other secondary metabolites. In vitro and in vivo pharmacological studies on the crude extracts, fractions, and isolated compounds from Lagochilus species showed hemostatic, antibacterial, anti-inflammatory, anti-allergic, cytotoxic, enzyme inhibitory, antispasmodic, hypotensive, sedative, psychoactive, and other activities.

Nose-to-brain delivery of amisulpride-loaded lipid-based poloxamer-gellan gum nanoemulgel: In vitro and in vivo pharmacological studies

2021 ◽  
Vol 607 ◽  
pp. 121050
Author(s):  
Dnyandev Gadhave ◽  
Shrikant Tupe ◽  
Amol Tagalpallewar ◽  
Bapi Gorain ◽  
Hira Choudhury ◽  
...  
Keyword(s):  
Gellan Gum ◽  
Brain Delivery ◽  
Pharmacological Studies

scholarly journals The Whisking Rhythm Generator: A Novel Mammalian Network for the Generation of Movement

2007 ◽  
Vol 97 (3) ◽  
pp. 2148-2158 ◽  
Author(s):  
Nathan P. Cramer ◽  
Ying Li ◽  
Asaf Keller
Keyword(s):  
Firing Rate ◽  
Serotonin Receptor ◽  
Central Pattern Generators ◽  
Rhythm Generator ◽  
Low Concentrations ◽  
Rhythmic Firing ◽  
Pattern Generators ◽  
Cortical Inputs

Using the rat vibrissa system, we provide evidence for a novel mechanism for the generation of movement. Like other central pattern generators (CPGs) that underlie many movements, the rhythm generator for whisking can operate without cortical inputs or sensory feedback. However, unlike conventional mammalian CPGs, vibrissa motoneurons (vMNs) actively participate in the rhythmogenesis by converting tonic serotonergic inputs into the patterned motor output responsible for movement of the vibrissae. We find that, in vitro, a serotonin receptor agonist, α-Me-5HT, facilitates a persistent inward current (PIC) and evokes rhythmic firing in vMNs. Within each motoneuron, increasing the concentration of α-Me-5HT significantly increases the both the magnitude of the PIC and the motoneuron's firing rate. Riluzole, which selectively suppresses the Na+ component of PICs at low concentrations, causes a reduction in both of these phenomena. The magnitude of this reduction is directly correlated with the concentration of riluzole. The joint effects of riluzole on PIC magnitude and firing rate in vMNs suggest that the two are causally related. In vivo we find that the tonic activity of putative serotonergic premotoneurons is positively correlated with the frequency of whisking evoked by cortical stimulation. Taken together, these results support the hypothesized novel mammalian mechanism for movement generation in the vibrissa motor system where vMNs actively participate in the rhythmogenesis in response to tonic drive from serotonergic premotoneurons.

scholarly journals Pharmacological studies on the laxative effects of Fagonia indica on rodents

2019 ◽  
Vol 14 (4) ◽  
pp. 166-173
Author(s):  
Muhammad Zeeshan Ali ◽  
Malik Hassan Mehmood ◽  
Muhammad Saleem ◽  
Anwar-ul-Hassan Gilani
Keyword(s):  
Ursolic Acid ◽  
Video Clip ◽  
In Vitro Assays ◽  
Aqueous Fraction ◽  
Laxative Effects ◽  
Pharmacological Studies ◽  
Full Screen ◽  
Species Specific

This study explores the pharmacological basis for the folk use of Fagonia indica in constipation using in vivo and in vitro assays. The crude extract of F. indica contained tannins, saponins, anthraquinones, alkaloids, flavonoids, glycosides and phenols. The administration of F. indica extract (100 and 300 mg/kg) to mice caused a partially atropine-sensitive 35 and 42.6% laxation, respectively, similar to ursolic acid which showed 22 and 36% laxation at 10 and 30 mg/kg, respectively. In loperamide-induced constipation mice, F. indica (27.3 and 34.6%) and ursolic acid (15 and 28%) also displayed laxative effects at the aforementioned doses. In mice and rats ileum, F. indica, its fractions (ethyl acetate, aqueous) and ursolic acid produced atropine-sensitive stimulatory effects, while in rats ileum, F. indica and aqueous fraction showed partially atropine-sensitive effects. F. indica and ursolic acid possess laxative and species-specific gut stimulant effects predominantly involving the activation of muscarinic receptor, thus eliciting its folk use in constipation. Video Clip of Methodology: 7 min 7 sec:  Full Screen   Alternate

An experimental in vitro model for evaluating drugs against protoscoleces of Echinococcus granulosus

1990 ◽  
Vol 64 (4) ◽  
pp. 343-348 ◽  
Author(s):  
Rodolfo Lorenzini ◽  
Anna Ruggieri
Keyword(s):  
Propylene Glycol ◽  
Echinococcus Granulosus ◽  
Low Concentrations ◽  
Pharmacological Studies ◽  
Human Sera ◽  
Human Therapy ◽  
Potential Activity ◽  
Vitro Model

ABSTRACTPharmacological studies carried out on protoscoleces in vitro to standardize conditions that would permit a preliminary estimate of the efficacy of drugs with potential activity against Echinococcus granulosus are reported. Media such as PBS and Hanks solution, maintenance temperature, different pH values and concentrations of various solvents have been tested to check the effects on protoscolex survival in tubes in vitro. Mebendazole has been used as the pharmacological standard reference. Changes in the viability of protoscoleces have been used to demonstrate pharmacological activity. Best conditions were obtained employing Hanks solution and propylene glycol at low concentrations. Mebendazole was not completely effective at the concentrations achievable in human therapy. Linear, reproducible results demonstrated that Hanks solution provides an ideal medium for pharmacological studies. Among tested solvents, propylene glycol and dimethyl sulphoxide showed no lethal activity at low concentrations. At concentrations similar to those normally obtained in human sera, mebendazole, as in vivo, demonstrated only partial lethality for protoscoleces. The present study represents a new experimental approach to chemotherapy of hydatid disease.

scholarly journals Analysis of pre- and postsynaptic factors of the serotonin system in rabbit retina.

1985 ◽  
Vol 100 (1) ◽  
pp. 64-73 ◽  
Author(s):  
C K Mitchell ◽  
D A Redburn
Keyword(s):  
Serotonin Receptor ◽  
Amacrine Cells ◽  
Uptake System ◽  
Rabbit Retina ◽  
Binding Studies ◽  
High Affinity ◽  
Serotonin System ◽  
Significant Difference

[3H]Serotonin is accumulated by a specific set of amacrine cells in the rabbit retina. These cells also accumulate the neurotoxin, 5,7-dihydroxytryptamine, and show signs of necrosis within 4 h of in vivo exposure to the drug. Biochemical analysis of [3H]serotonin uptake reveal a sodium- and temperature-dependent, high affinity uptake system with a Km of 0.94 microM and Vmax of 1.08 pmol/mg protein/min. [3H]Tryptophan is also accumulated in rabbit retinal homogenates by a high affinity process. Accumulated [3H]serotonin is released in response to potassium-induced depolarization of intact, isolated retinas. In vitro binding studies of rabbit retinal homogenate membranes demonstrate specific sets of binding sites with characteristics of the postsynaptic serotonin receptor. These data strongly suggest that rabbit retina contains virtually all of the molecular components required for a functional serotonergic neurotransmitter system. The only significant difference between the serotonin system in rabbit retina and that in the well-established serotonin transmitter systems in nonmammalin retinas and in brains of most species is the relatively low concentration of endogenous serotonin in rabbit retinas, as demonstrated by high-performance liquid chromatography, histofluorescence, or immunocytochemistry.

scholarly journals Betamethasone Induces a Unique Transcriptome in Neural Stem Cells

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A802-A802
Author(s):  
Neerupma Silswal ◽  
Joe Bean ◽  
Herschel Gupta ◽  
Fatma Talib ◽  
Suban Burale ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Serotonin Receptor ◽  
Target Genes ◽  
Biological Response ◽  
The United States ◽  
Oligodendrocyte Differentiation

Abstract Twelve percent of pregnant women receive glucocorticoids (sGCs) to reduce the risks to reduce morbidity and mortality associated with preterm birth in infants. The two most commonly administered sGC are Dexamethasone (Dex) and Betamethasone (Beta) and they serve to decrease the severity of respiratory distress, intraventricular hemorrhage and necrotizing enterocolitis. However, repeated administration of sGC has been shown to be associated with adverse neurological outcome and depends on the type of sGCs used, dose, timing of sGCs administration and sex. We have previously shown that prenatal exposure to Dex in a murine model lead to sex specific changes in the transcription response and in the biological function of neural stem cells and to long-term changes in brain architecture and behavior. Beta is the predominant sGC used prenatally in the United States, therefore these studies investigated the cellular and molecular responses to beta exposure on the neural stem cells in-vitro and anatomical organization of the brain in-vivo. Murine NSCs were isolated from the E14.5 cerebral cortex and exposed to 10-7 M Dex, 10-7 M Beta, or Vehicle for 4 or 24 hours and the immediate and long-term impact on transcription, proliferation and neuronal, glial and oligodendrocyte differentiation examined. Affymetrix genome transcriptional analyses reveal sex specific responses to Dex vs Beta in 4 hours. In females 682 genes were differentially regulated by Dex compared to 576 by Beta. In contrast, 875 were altered by Dex and 576 by Beta in males (Fold change > +/- 1.5, P< 0.05). Select target genes were independently validated by QPCR. Ingenuity Pathway Analysis was used to identify unique and overlapping pathways that were altered by Dex vs Beta. In males, Dex uniquely altered 34 pathways including, Thyroid Hormone Metabolism, ERK5 Signaling and Opioid Signaling while Bata altered 33 pathways including, Phagasome formation, IL-7 Signaling and JAK STAT signaling. In Females, Dex altered 45 pathways including Calcium Signaling, Serotonin Receptor Signaling and Xenobiotic Signaling, while Beta altered 46 pathways including, FXR/RXR Activation, Tec Kinase Signaling and D-myo-Inositol-5-Phosphate Metabolism. Another 35 pathways were altered by both Dex and Beta but they showed differences in genes activated or repressed. Dex and Beta, both significantly altered genes involved in proliferation and differentiation therefore the biological response of NSC to sGCs stimulation in vitro and the long term consequences of sGC exposure in-vivo was compared. Distinct differences in cell proliferation, glial and oligodendrocyte differentiation were observed. These results reveal gene targets, cellular pathways and processes that are differentially altered by prenatal Dex vs Beta exposure. Our finds may provide insights into the sex specific neurological outcomes observed in children exposed to sGCs in-utero.

scholarly journals The Potential Anti-Inflammatory Effects of Brucea javanica (L.) Merr.

2021 ◽  
Vol 6 (9) ◽  
pp. 1-7
Author(s):  
Sisi Mustika ◽  
Sri Oktavia ◽  
Ifora Ifora
Keyword(s):  
Mrna Expression ◽  
Initial Response ◽  
In Vivo Studies ◽  
Brucea Javanica ◽  
Ppar Γ ◽  
Pharmacological Studies ◽  
Ifn Γ ◽  
Anti Inflammatory

Inflammation is the initial response to acute and chronic tissue damage, which is characterized by redness, swelling, heat, and pain. Natural products derived from plants have specific pharmacological activity and minimal side effects. Brucea javanica is a plant that has an anti-inflammatory effect, this plant contains alkaloid and flavonoid compounds. Flavonoids have the ability to block cyclooxygenase and lipoxygenase while alkaloids as an anti-inflammatory are thought to work by inhibiting prostaglandin H2 PGH2 which is an inflammatory mediator. From the data obtained, there is no complete literature that reviews its use as an anti-inflammatory. The search databases used are as follows: Pubmed, ScienceDirect, and Google Scholar to study the anti-inflammatory activity of Brucea javanica. All recent research articles were published between 2010 to 2021. Based on eligibility, 4 studies were included in this study, consisting of 2 In vivo studies and 2 In vitro and In vivo studies. A series of pharmacological studies have reported that Brucea javanica can block the Nf-kB signaling pathway and decrease the production of inflammatory mediators. It has been reported to be able to inhibit the production of NO, PGE2, TNF-, IL-1β, IL-18IL-23, COX-2, NF-κB, IFN-γ, IL-6, the levels of MPO (Myeloperoxidase), reducing the edema and induce the production of the anti-inflammatory cytokine (IL-4, IL-10 and TGF-β). Brucea javanica also markedly activates Nrf2 expression suppressing the inflammatory response-mediated NLRP3 and NF-κB activation. In addition, the elevated mRNA expression of MMP-1, MMP-3 and RAGE was remarkably inhibited by Brucea javanica, while the mRNA expression of PPAR-γ was significantly enhanced. In vitro and in vivo studies strongly indicate that Brucea javanica has the potential as an anti-inflammatory.

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