Physical compatibility and chemical stability of dezocine and ramosetron in 0.9% sodium chloride injection for patient-controlled analgesia administration.

As an antiemetic, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist (ramosetron) is generally administered to prevent and treat postoperative nausea and vomiting induced by intravenous dezocine for patient-controlled analgesia. To date, the physicochemical stability of dezocine-ramosetron admixtures has not been assessed. The primary objective of this study was to evaluate the physicochemical stability of a combination of dezocine and ramosetron in 0.9% sodium chloride (normal saline [NS]) injections. Dezocine-ramosetron admixtures were prepared and stored in glass bottles and polyvinyl chloride (PVC) bags refrigerated at 4°C or stored at ambient temperatures (25°C) for up to 14 days. Initial concentrations were 5.0 mg/100 mL for dezocine and 0.3 mg/100 mL for ramosetron used as the diluents. Stability parameters (drug concentrations and pH values) were determined using high-performance liquid chromatography and pH measurements, respectively. Compatibility (cloudiness, discoloration, and precipitation) was assessed visually. After 14 days at 4 °C or 25 °C, the concentration losses of dezocine and ramosetron were both < 4%. Furthermore, there were no significant changes in color, turbidity, or pH values were observed in any of the batches. The results indicated that mixtures of dezocine and ramosetron in NS injections were continuously physically and chemically stable for 14 days in glass bottles or PVC bags stored at 4 °C or 25 °C.

Hydroxy Pentacyclic Triterpene Acid, Kaempferol, Inhibits the Human 5-Hydroxytryptamine Type 3A Receptor Activity.

Monoamine serotonin is a major neurotransmitter that acts on a wide range of central nervous system and peripheral nervous system functions and is known to have a role in various processes. Recently, it has been found that 5-HT is involved in cognitive and memory functions through interaction with cholinergic pathways. The natural flavonoid kaempferol (KAE) extracted from Cudrania tricuspidata is a secondary metabolite of the plant. Recently studies have confirmed that KAE possesses a neuroprotective effect because of its strong antioxidant activity. It has been confirmed that KAE is involved in the serotonergic pathway through an in vivo test. However, these results need to be confirmed at the molecular level, because the exact mechanism that is involved in such effects of KAE has not yet been elucidated. Therefore, the objective of this study is to confirm the interaction of KAE with 5-HT3A through electrophysiological studies at the molecular level using KAE extracted from Cudrania tricuspidata. This study confirmed the interaction between 5-HT3A and KAE at the molecular level. KAE inhibited 5-HT3A receptors in a concentration-dependent and voltage-independent manner. Site-directed mutagenesis and molecular-docking studies confirmed that the binding sites D177 and F199 are the major binding sites of human 5-HT3A receptors of KAE.

The Binding of Palonosetron and Other Antiemetic Drugs to the Serotonin 5-HT3 Receptor.

Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting. These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryoelectron microscopy structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.

Mapping the Orthosteric Binding Site of the Human 5-HT3 Receptor Using Photo-cross-linking Antagonists.

The serotonin-gated 5-HT3 receptor is a ligand-gated ion channel. Its location at the synapse in the central and peripheral nervous system has rendered it a prime pharmacological target, for example, for antiemetic drugs that bind with high affinity to the neurotransmitter binding site and prevent the opening of the channel. Advances in structural biology techniques have led to a surge of disclosed three-dimensional receptor structures; however, solving ligand-bound high-resolution 5-HT3 receptor structures has not been achieved to date. Ligand binding poses in the orthosteric binding site have been largely predicted from mutagenesis and docking studies. We report the synthesis of a series of photo-cross-linking compounds whose structures are based on the clinically used antiemetic drug granisetron (Kytril). These displaced [3H]granisetron from the orthosteric binding site with low nanomolar affinities and showed specific photo-cross-linking with the human 5-HT3 receptor. Detailed analysis by protein-MS/MS identified a residue (Met-228) near the tip of binding loop C as the covalent modification site.

QSAR Analysis of Multimodal Antidepressants Vortioxetine Analogs Using Physicochemical Descriptors and MLR Modeling.

BACKGROUND: Vortioxetine is a multimodal antidepressant drug with combined effects on SERT as an inhibitor, 5-HT1A as agonist and 5-HT3A as an antagonist. Series of vortioxetine analogs have been reported as multi antidepressant compounds and they block serotonin transport into the neuronal cells, activate the postsynaptic 5-HT1A receptors and eliminate the low activity of 5-HT3A receptors. OBJECTIVE: To explore the important properties of vortioxetine analogs involved in antidepressant activity by developing 2D QSAR models. METHODS: Selections of significant descriptors were performed by Least Absolute Shrinkage and Selection Operator (LASSO) method and, the Multiple Linear Regression (MLR) method and All Subsets and GA algorithm included in QSARINS software were used for generating QSAR models. Further, the virtual screening was performed based on bioactivity and structure similarity using the PubChem database. RESULTS: The four descriptor model of complementary information content (CIC2), solubility (bcutp3), mass (bcutm8) and partial charge in van der Waals surface area (PEOEVSA7) of the molecules is obtained for SERT inhibition with the significant statistics of R2= 0.69, RMSEtr= 0.44, R2 ext= 0.62 and CCCext= 0.78. For 5-HT1A agonist, the two descriptor model of molecular shape (Kappm3) and van der Waals volume of the atoms (bcutv11) with R2= 0.78, RMSEtr= 0.33, R2 ext = 0.83, and CCCext= 0.87 is established. The three descriptor model of information content (IC3), solubility (bcutp9) and electronegativity (GATSe5) of the molecules with R2= 0.61, RMSEtr= 0.34, R2 ext= 0.69 and CCCext= 0.72 is obtained for 5-HT3A antagonist. The antidepressant activities of 16 virtual screened compounds were predicted using the developed models. CONCLUSION: The developed QSAR models may be useful to predict antidepressant activity for the newly synthesized vortioxetine analogs.

"Methylene Bridge" to 5-HT3 Receptor Antagonists: Conformationally Constrained Phenylguanidines.

Arylguanidines, depending upon their aromatic substitution pattern, display varying actions at 5-HT3 receptors (e.g., partial agonist, agonist, superagonist). Here, we demonstrate that conformational constraint of these agents as dihydroquinazolines (such as A6CDQ; 1) results in their conversion to 5-HT3 receptor antagonists. We examined the structure-activity relationships of 1. Replacement/removal of any of the guanidinium nitrogen atoms of 1 resulted in decreased affinity. All three nitrogen atoms of 1 are necessary for optimal binding affinity at 5-HT3 receptors. Introduction of substituents as small as an N2-methyl group abolishes affinity. The results are consistent with homology modeling/docking studies and binding data from site-directed mutagenesis studies. Introducing a "methylene bridge" to the arylguanidine structure, regardless of its functional activity, results in a 5-HT3 receptor antagonist.

Compatibility and stability of dezocine and tropisetron in 0.9% sodium chloride injection for patient-controlled analgesia administration.

Tropisetron is an adjuvant for dezocine used in intravenous patient-controlled analgesia (PCA) and has been reported to provide superior pain control. It is efficacious in reducing the institutional incidence of postoperative nausea and vomiting (PONV), which decreases resource utilization and cost. However, no scientific evidence has been reported in the literature demonstrating analytical confirmation of the compatibility and stability of the combination of dezocine and tropisetron. Thus, the present study aimed to investigate the stability of dezocine with tropisetron in 0.9% sodium chloride injection form for PCA administration.Commercial solutions of dezocine and tropisetron were combined and examined for compatibility and stability when diluted with 0.9% sodium chloride injection in polyolefin bags and glass bottles stored at 4°C or 25°C for up to 14 days. The initial concentrations were 40 mg/100 mL dezocine and 5 mg/100 mL tropisetron. For all samples, the compatibility parameters (including precipitation, cloudiness, discoloration, and pH values) were evaluated. Chemical stability was also determined using high-performance liquid chromatographic (HPLC) analysis.After a 14-day period of storage at 4°C or 25°C, the initial concentrations of dezocine and tropisetron were maintained at at least 98%. All of the mixtures remained clear and colorless throughout the observation period, and no color change or precipitation was observed.These results indicated that admixtures of 40 mg/100 mL dezocine and 5 mg/100 mL tropisetron in 0.9% sodium chloride injection were stable for at least 14 days when stored in polyolefin bags or glass bottles at 4°C or 25°C and protected from light.

Natural Negative Allosteric Modulators of 5-HT3 Receptors.

Chemotherapy-induced nausea and vomiting (CINV) remain the most common and devastating side-effects associated with cancer chemotherapy. In recent decades, several lines of research emphasize the importance of 5-hydroxytryptamine3 (5-HT3; serotonin) receptors in the pathogenesis and treatment of CINV. 5-HT3 receptors are members of ligand-gated ion channels that mediate the rapid and transient membrane-depolarizing effect of 5-HT in the central and peripheral nervous system. These receptors play important roles in nausea and vomiting, as well as regulation of peristalsis and pain transmission. The development of antagonists for 5-HT3 receptor dramatically improved the treatment of CINV in cancer patients. In fact, the most common use of 5-HT3 receptor antagonists to date is the treatment of nausea and vomiting. In recent years, there has been an increasing tendency to use natural plant products as important therapeutic entities in the treatment of various diseases. In this article, we examined the results of earlier studies on the actions of natural compounds on the functional properties of 5-HT3 receptors. It is likely that these natural modulators of 5-HT3 receptors can be employed as lead structures for the synthesis of therapeutic agents for treating CINV in future clinical studies.

Compatibility and Stability of VARUBI (Rolapitant) Injectable Emulsion Admixed with Intravenous Granisetron Hydrochloride.

Prophylaxis or therapy with a combination of a neurokinin 1 (NK-1) receptor antagonist (RA), a 5-hydroxytryptamine- 3 (5-HT3) RA, and dexamethasone is recommended by international antiemesis guidelines for the prevention of chemotherapy-induced nausea and vomiting for patients receiving highly emetogenic chemotherapy and for select patients receiving moderately emetogenic chemotherapy. VARUBI (rolapitant) is a substance P/NK-1 RA that was recently approved by the U.S. Food and Drug Administration as an injectable emulsion in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Granisetron Hydrochloride Injection USP is one of the 5-HT3 RAs indicated for the prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin. Herein, we describe the physical and chemical compatibility and stability of VARUBI (rolapitant) injectable emulsion (166.5 mg/92.5 mL [1.8 mg/mL], equivalent to 185 mg of rolapitant hydrochloride) admixed with Granisetron Hydrochloride Injection USP (1.0 mg/mL, equivalent to 1.12 mg/mL hydrochloride). Binary admixtures of VARUBI injectable emulsion and Granisetron Hydrochloride Injection USP were prepared and stored in VARUBI ready-to-use glass vials and in four types of commonly used intravenous administration (tubing) sets. Evaluation of the physical and chemical compatibility and stability of the admixtures in the VARUBI ready-to-use vials stored at room temperature (20°C to 25°C) under fluorescent light and under refrigeration (2°C to 8°C protected from light) was conducted at 0, 1, 6, 24, and 48 hours, and that of the admixtures in the intravenous tubing sets was evaluated at 0, 2, and 6 hours of storage at 20°C to 25°C. Physical stability was evaluated by visual examination of the container contents under normal room light, and measurement of turbidity, globule size, and particulate matter. Chemical stability was assessed by measuring the pH of the admixture and determining drug concentrations (potency) and impurity levels by high-performance liquid chromatographic analysis. The pH, turbidity, globule size, and particulate matter of all samples remained within narrow and acceptable ranges at all study time points, indicating that combining the two formulations into a binary admixture is physically and chemically compatible and stable. VARUBI injectable emulsion admixed with Granisetron Hydrochloride Injection USP demonstrated compatibility and stability in a ready-to-use glass vial for at least 24 hours at room temperature and 48 hours under refrigeration, as well as in the four intravenous tubing sets for at least 6 hours at 20°C to 25°C. No decrease of drug concentration (or potency) of any admixed components occurred in the samples stored at the two conditions and time periods studied based on high-performance liquid chromatographic analysis. The levels of impurities stayed below the safety limits set by International Conference on Harmonisation during the study period.

Compatibility and Stability of VARUBI (Rolapitant) Injectable Emulsion Admixed with Intravenous Palonosetron Hydrochloride Injection and Dexamethasone Sodium Phosphate Injection.

Prophylaxis or therapy with a combination of a neurokinin 1 (NK-1) receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone is recommended by international antiemesis guidelines for the prevention of chemotherapy-induced nausea and vomiting for patients receiving highly emetogenic chemotherapy and for selected patients receiving moderately emetogenic chemotherapy. VARUBI (rolapitant) is a substance P/NK-1 RA that was recently approved by the U.S. Food and Drug Administration as an injectable emulsion in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Palonosetron is one of the 5-HT3 RAs indicated for the prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin. Herein, we describe the physical and chemical compatibility and stability of VARUBI injectable emulsion (166.5 mg/92.5 mL [1.8 mg/mL, free base], equivalent to 185 mg of rolapitant hydrochloride) admixed with palonosetron injection 0.25 mg free base in 5 mL (equivalent to 0.28 mg hydrochloride salt) and with either 5 mL (20 mg) or 2.5 mL (10 mg) of dexamethasone sodium phosphate. Admixtures were prepared and stored in VARUBI injectable emulsion ready-to-use glass vials as supplied by the rolapitant manufacturer and in four types of commonly used intravenous administration (tubing) sets. Assessment of the physical and chemical compatibility and stability of the admixtures in the VARUBI ready-to-use vials stored at room temperature (20°C to 25°C) under fluorescent light and under refrigeration (2°C to 8°C protected from light) was conducted at 0, 1, 6, 24, and 48 hours, and that of the admixtures in the intravenous tubing sets was evaluated at 0, 2, and 6 hours of storage at 20°C to 25°C. Physical stability was evaluated by visual examination of the container contents under normal room light, and measurement of turbidity, globule size, and particulate matter. Chemical stability was assessed by measuring the pH of the admixture and determining drug concentrations (potency) and impurity levels by high-performance liquid chromatographic analysis. All samples were physically and chemically compatible throughout the study duration. The pH, turbidity, globule size, and particulate matter of the admixture stayed within narrow and acceptable ranges. VARUBI injectable emulsion admixed with intravenous palonosetron and dexamethasone was chemically and physically stable in the ready-to-use glass vials for at least 24 hours at room temperature and 48 hours under refrigeration, as well as in the four selected intravenous tubing sets for at least 6 hours at room temperature. No decrease of drug concentration (or potency) of any admixed components occurred in the samples stored at the two temperature ranges and time periods studied as measured by high-performance liquid chromatographic analysis.

Palonosetron-5-HT3 Receptor Interactions As Shown by a Binding Protein Cocrystal Structure.

Palonosetron is a potent 5-HT3 receptor antagonist and an effective therapeutic agent against emesis. Here we identify the molecular determinants of compound recognition in the receptor binding site by obtaining a high resolution structure of palonosetron bound to an engineered acetylcholine binding protein that mimics the 5-HT3 receptor binding site, termed 5-HTBP, and by examining the potency of palonosetron in a range of 5-HT3 receptors with mutated binding site residues. The structural data indicate that palonosetron forms a tight and effective wedge in the binding pocket, made possible by its rigid tricyclic ring structure and its interactions with binding site residues; it adopts a binding pose that is distinct from the related antiemetics granisetron and tropisetron. The functional data show many residues previously shown to interact with agonists and antagonists in the binding site are important for palonosetron binding, and indicate those of particular importance are W183 (a cation-π interaction and a hydrogen bond) and Y153 (a hydrogen bond). This information, and the availability of the structure of palonosetron bound to 5-HTBP, should aid the development of novel and more efficacious drugs that act via 5-HT3 receptors.

Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT3) Subunit A Receptors.

Introduction of minor variations to the substitution pattern of arylguanidine 5-hydroxytryptamine-3 (5-HT3) receptor ligands resulted in a broad spectrum of functionally-active ligands from antagonist to superagonist. For example, (i) introduction of an additional Cl-substituent(s) to our lead full agonist N-(3-chlorophenyl)guanidine (mCPG, 2; efficacy % = 106) yielded superagonists 7-9 (efficacy % = 186, 139, and 129, respectively), (ii) a positional isomer of 2, p-Cl analog 11, displayed partial agonist actions (efficacy % = 12), and (iii) replacing the halogen atom at the meta or para position with an electron donating OCH3 group or a stronger electron withdrawing (i.e., CF3) group resulted in antagonists 13-16. We posit based on combined mutagenesis, crystallographic, and computational analyses that for the 5-HT3 receptor, the arylguanidines that are better able to simultaneously engage the primary and complementary subunits, thus keeping them in close proximity, have greater agonist character while those that are deficient in this ability are antagonists.

Stability of tramadol with three 5-HT3 receptor antagonists in polyolefin bags for patient-controlled delivery systems.

BACKGROUND: Mixing 5-hydroxytryptamine-3 (5-HT3) receptor antagonists with patient-controlled analgesia (PCA) solutions of tramadol has been shown to decrease the incidence of nausea and vomiting associated with the use of tramadol PCA for postoperative pain. However, such mixtures are not commercially available, and the stability of the drug combinations has not been duly studied. The study aimed to evaluate the stability of tramadol with three 5-HT3 receptor antagonists in 0.9% sodium chloride injection for PCA administration. MATERIALS AND METHODS: Test samples were prepared by adding 1,000 mg tramadol hydrochloride, 8 mg ondansetron hydrochloride, and 6 mg granisetron hydrochloride or 5 mg tropisetron hydrochloride to 100 mL of 0.9% sodium chloride injection in polyolefin bags. The samples were prepared in triplicates, stored at either 25°C or 4°C for 14 days, and assessed using the following compatibility parameters: precipitation, cloudiness, discoloration, and pH. Chemical stability was also determined using a validated high-pressure liquid chromatography method. RESULTS: All of the mixtures were clear and colorless throughout the initial observation period. No change in the concentration of tramadol hydrochloride occurred with any of the 5-HT3 receptor antagonists during the 14 days. Similarly, little or no loss of the 5-HT3 receptor antagonists occurred over the 14-day period. CONCLUSION: Our results suggest that mixtures of tramadol hydrochloride, ondansetron hydrochloride, granisetron hydrochloride, or tropisetron hydrochloride in 0.9% sodium chloride injection were physically and chemically stable for 14 days when stored in polyolefin bags at both 4°C and 25°C.

Antidepressant & anxiolytic activities of N-(pyridin-3-yl) quinoxalin-2-carboxamide: A novel serotonin type 3 receptor antagonist in behavioural animal models.

BACKGROUND & OBJECTIVES: Alteration in the serotonin leads to the psychological illness, such as depression, anxiety, schizophrenia, eating disorders, obsessive-compulsive disorder, panic disorders and migraines. The objective of the current study was to investigate the antidepressant and anxiolytic activities of N-(pyridin-3-yl) quinoxalin-2-carboxamide (QCF-21), a novel 5-HT3receptor antagonist in preclinical models of depression and anxiety. METHODS: Antidepressant activity was evaluated in preliminary tests such as forced swim and tail suspension tests (FST & TST). Anti-anxiety effect of QCF-21 was investigated by employing elevated plus maze (EPM), light/dark and hole board tests. Olfactory bulbectomy (OBX) in rats was used as chronic model of depression. Mechanistic test of QCF-21 was evaluated by reserpine-induced hypothermia and 5-hydroxytryptophan (5-HTP)-induced head-twitch response. RESULTS: The dose-response study revealed an initial antidepressant-like effect of QCF-21(0.25-1 mg/kg, i.p.) in the FST and TST and anxiolytic-like effect in EPM, light and dark and hole board tests. QCF-21 potentiated the 5-HTP-induced head-twitches response in mice and reversed reserpine-induced hypothermia in rats. QCF-21 significantly reversed the behavioural anomalies post-OBX in rats. INTERPRETATION & CONCLUSIONS: The present findings indicate the potential antidepressant-like and anxiolytic-like effects of QCF-21 at low doses in rodent behavioural models of depression and anxiety. Further studies need to be done to understand the underlying mechanism.

Noncompetitive Inhibition of 5-HT3 Receptors by Citral, Linalool, and Eucalyptol Revealed by Nonlinear Mixed-Effects Modeling.

Citral, eucalyptol, and linalool are widely used as flavorings, fragrances, and cosmetics. Here, we examined their effects on electrophysiological and binding properties of human 5-HT3 receptors expressed in Xenopus oocytes and human embryonic kidney 293 cells, respectively. Data were analyzed using nonlinear mixed-effects modeling to account for random variance in the peak current response between oocytes. The oils caused an insurmountable inhibition of 5-HT-evoked currents (citral IC50 = 120 µM; eucalyptol = 258 µM; linalool = 141 µM) and did not compete with fluorescently labeled granisetron, suggesting a noncompetitive mechanism of action. Inhibition was not use-dependent but required a 30-second preapplication. Compound washout caused a slow (∼180 seconds) but complete recovery. Coapplication of the oils with bilobalide or diltiazem indicated they did not bind at the same locations as these channel blockers. Homology modeling and ligand docking predicted binding to a transmembrane cavity at the interface of adjacent subunits. Liquid chromatography coupled to mass spectrometry showed that an essential oil extracted from Lippia alba contained 75.9% citral. This inhibited expressed 5-HT3 receptors (IC50 = 45 µg ml(-1)) and smooth muscle contractions in rat trachea (IC50 = 200 µg ml(-1)) and guinea pig ileum (IC50 = 20 µg ml(-1)), providing a possible mechanistic explanation for why this oil has been used to treat gastrointestinal and respiratory ailments. These results demonstrate that citral, eucalyptol, and linalool inhibit 5-HT3 receptors, and their binding to a conserved cavity suggests a valuable target for novel allosteric modulators.

A novel 5HT3 antagonist 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide) prevents diabetes-induced depressive phenotypes in mice: Modulation of serotonergic system.

Despite the presence of a multitudinous pharmacotherapy, diabetes-induced depressive disorder remains undertreated. Evidence suggests that brain serotonergic deficits are associated with depressive-like behavior in diabetes and that 5HT3 receptor (5HT3R) antagonists have serotonergic facilitatory effects. This study examined the effects of a novel 5HT3R antagonist, 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide), in diabetes-induced depressive phenotypes. Experimentally, (1) to evaluate the effects of 4i, mice with 8-weeks of diabetes (induced by streptozotocin, 200mg/kg, i.p.) were treated with vehicle, 4i (0.5 and 1mg/kg/day, i.p.), fluoxetine (10mg/kg/day, i.p.) for 4-weeks and subjected to neurobehavioral assays, followed by biochemical estimation of serotonin levels in midbrain, prefrontal-cortex and cerebellum. (2) To evaluate the role of 5HT3R in the postulated effect of 4i, diabetic mice were given 4i (1mg/kg/day, i.p.) after 1h of 1-(m-chlorophenyl)-biguanide (mCPBG, a 5HT3R agonist, 10mg/kg/day, i.p.) treatment and subjected to the same protocol. The results showed that diabetic mice exhibited a significant behavioral deficit, including depression-like behavior in forced swim test, anxiety-like in open field test and sociability deficits in social interaction test, along with a significant decrease in serotonin level in these brain regions. 4i (1mg/kg), similar to fluoxetine, prevented these behavioral abnormalities and normalized brain serotonin levels. 4i (0.5mg/kg) ameliorated only diabetes-induced depressive-like behavior and serotonin deficits, but not anxiety-like effects. mCPBG blunted 4i-mediated behavioral response and increase in brain serotonin levels. Altogether, this study suggests that 4i prevents diabetes-induced depressive phenotypes in mice, which may involve antagonism of 5HT3Rs and increase in serotonin levels in discrete brain regions.

Design of α7 nicotinic acetylcholine receptor ligands using the (het)Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies.

We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as α7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for α7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH2F groups or fluorine atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes. Among the 30 derivatives tested, the two derivatives 10 and 39 with Ki in the nanomolar range were identified (2.3 and 3 nM respectively). They exhibited a strict selectivity toward the α4ß2 nicotinic receptor (up to 1 µM) but interacted with the 5HT3 receptors with Ki around 3 nM. Synthesis, SAR studies and a full description of the derivatives are reported.

Effects of ramosetron oral disintegrating tablets on gastric emptying: crossover study using the 13C-acetic acid breath test.

BACKGROUND/AIMS: Ramosetron is a new selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist that reportedly has more potent antiemetic effects than other 5-HT3 receptor antagonists. The aim of this study was to determine the effect of ramosetron pretreatment on gastric emptying using the 13C-acetic acid breath test. METHODOLOGY: Ten healthy male and female volunteers participated in this randomized, twoway crossover study. After they had fasted overnight, the subjects were randomly assigned to receive 0.1 mg ramosetron 1 hour before ingestion of a test meal (200 kcal per 200 mL, containing 100 mg 13C acetate) or to receive the test meal alone. Under both conditions, breath samples were collected for 150 min following ingestion of the meal. Statistical comparison of the parameters between the two test conditions was performed. RESULTS: No significant differences in the calculated parameters, including T 1/2, T lag, GEC or ß and κ, were observed between the two test conditions. CONCLUSIONS: The present study revealed that 0.1 mg ramosetron had no significant effect on the rate of gastric emptying. Thus, our results suggest that ramosetron can be administered safely, without gastrointestinal adverse effects, even to terminal cancer patients with delayed or accelerated gastric emptying abnormality.

Procognitive properties of drugs with single and multitargeting H3 receptor antagonist activities.

The histamine H3 receptor (H3 R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H3 R antagonists/inverse agonists involved studies of structure-activity relationships, cross-affinities, and pharmacokinetic properties of promising ligands. Blockade of inhibitory histamine H3 autoreceptors reinforces histaminergic transmission, while antagonism of H3 heteroreceptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma-aminobutyric acid (GABA). The H3 R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small-molecule H3 R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H3 R antagonism/inverse agonism with inhibition of acetylcholine esterase (AChE), histamine N-methyltransferase (HMT), or serotonin transporter (SERT) are novel class of procognitive agents. Main chemical diversities, pharmacophores, and pharmacological profiles of procognitive agents acting as H3 R antagonists/inverse agonists and dual H3 R antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here.