Day: November 21, 2022

Goura, Ramesh published the artcileImproved and ′Nitrosamines Free′ Process for the Preparation of an α4β2 Neuronal Nicotinic Acetylcholine Receptor Agonist-Varenicline Tartrate, HPLC of Formula: 375815-87-5, the publication is Polycyclic Aromatic Compounds, database is CAplus.

An improvised and efficient approach for synthesis of α4β2 nicotinic acetylcholine receptor subtype agonist, Varenicline tartrate free from the ′N-nitrosamines′ has been described. The approach involves an improved process for a key intermediate (7,8-dinitro-4,5-dihydro-1H-1,5-methanobenzo[d] azepin-3(2H)-yl)-2,2,2-trifluoro ethanone free from potential genotoxic impurities. Compound is converted into Varenicline base in a single pot process with improved overall yield and quality. Further, Varenicline base is converted into Varenicline tartrate by acid addition salt which provides in quant. yield. This improved process consists of tech. innovations/improvements which eliminate the probability for the formation of critical impurities such as dinitro nitroso impurity , diamino nitroso impurity and varenicline nitroso impurity and other genotoxic impurities such as mono nitro impurity and meta dinitro impurity in the final drug substance and provides ′Nitrosamines free′ varenicline tartrate with good quality and yield.

Polycyclic Aromatic Compounds published new progress about 375815-87-5. 375815-87-5 belongs to quinoxaline, auxiliary class Neuronal Signaling,AChR,Natural product, name is 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate, and the molecular formula is C17H19N3O6, HPLC of Formula: 375815-87-5.

Referemce:
https://en.wikipedia.org/wiki/Quinoxaline,
Quinoxaline | C8H6N2 | ChemSpider

Poornesh, Gowda A. S. published the artcileDevelopment and validation of analytical method for simultaneous estimation of varenicline tartrate and bupropion hydrochloride, Recommanded Product: 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate, the publication is World Journal of Pharmacy and Pharmaceutical Sciences (2019), 8(2), 925-937, database is CAplus.

A simple, sensitive, precise, rapid and accurate reverse phase high performance liquid chromatog. (RP-HPLC) method was developed and validated for simultaneous estimation of Varenicline tartrate and Bupropion hydrochloride. The Chromatog. separation was achieved by using Cosmosil C18 (250 mm × 4.6 mm, 5μ) as stationary phase and mobile phase consists of Methanol: phosphate buffer with pH 3.0 (65:35 volume/volume) with a flow rate of 1ml/min. The anal. was performed at ambient temperature and the eluent was monitored at 244 nm using UV detector. The retention time of Varenicline tartrate and Bupropion hydrochloride was found to be 3.0 min and 4.2 min resp. and the calibration curves were linear (r2 = 0.999 and 0.998) over a concentration range of 10-50μg/mL for Varenicline tartrate and 100-500μg/mL for Bupropion hydrochloride resp. The Limit of detection (LOD) for Varenicline tartrate and Bupropion hydrochloride was observed to be 0.002μg/mL and 0.006μg/mL resp., the limit of quantitation (LOQ) was found to be 0.006μg/mL and 0.018μg/mL resp. The developed method was validated as per ICH guidelines using parameters like linearity, specificity, system suitability, precision, ruggedness, robustness, accuracy. All the validation parameters were found to be well within the acceptance criteria. Hence the proposed method can be used for the routine anal. of Varenicline tartrate and Bupropion hydrochloride in bulk and tablet dosage forms.

World Journal of Pharmacy and Pharmaceutical Sciences published new progress about 375815-87-5. 375815-87-5 belongs to quinoxaline, auxiliary class Neuronal Signaling,AChR,Natural product, name is 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate, and the molecular formula is C17H19N3O6, Recommanded Product: 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate.

Referemce:
https://en.wikipedia.org/wiki/Quinoxaline,
Quinoxaline | C8H6N2 | ChemSpider

Vanejevs, Maksims published the artcilePositive and Negative Modulation of Group I Metabotropic Glutamate Receptors, Application In Synthesis of 226878-01-9, the publication is Journal of Medicinal Chemistry (2008), 51(3), 634-647, database is CAplus and MEDLINE.

A discriminating pharmacophore model for noncompetitive metabotropic glutamate receptor antagonists of subtype 1 (mGluR1) was developed that facilitated the discovery of moderately active mGluR1 antagonists. One scaffold was selected for the design of several focused libraries where different substitution patterns were introduced. This approach facilitated the discovery of potent mGluR1 antagonists, as well as pos. and neg. mGluR5 modulators, because both receptor subtypes share similar binding pockets. For mGluR1 antagonists, a homol. model of the mGlu1 receptor was established, and a putative binding mode within the receptor’s transmembrane domain was visualized.

Journal of Medicinal Chemistry published new progress about 226878-01-9. 226878-01-9 belongs to quinoxaline, auxiliary class Neuronal Signaling,mGluR, name is N-(Adamantan-1-yl)quinoxaline-2-carboxamide, and the molecular formula is C9H5ClO4S, Application In Synthesis of 226878-01-9.

Referemce:
https://en.wikipedia.org/wiki/Quinoxaline,
Quinoxaline | C8H6N2 | ChemSpider

Lavreysen, Hilde published the artcile[³H]R214127: A novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists, SDS of cas: 226878-01-9, the publication is Molecular Pharmacology (2003), 63(5), 1082-1093, database is CAplus and MEDLINE.

R214127 was shown to be a potent and noncompetitive metabotropic glutamate 1 (mGlu1) receptor-selective antagonist. The kinetics and pharmacol. of [³H]1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1- ethanone (R214127) binding to rat mGlu1a receptor Chinese hamster ovary (CHO)-dhfr^– membranes was investigated, as well as the distribution of [³H]R214127 binding in rat brain tissue and sections. Specific binding to rat mGlu1a receptor CHO-dhfr^– membranes was ∼92% of total and was optimal at 4°. Full association was reached within 5 min, and [³H]R214127 bound to a single binding site with an apparent K_D of 0.90 nM and a B_max of 6512 fmol/mg of protein. Inhibition experiments showed that [³H]R214127 binding was completely blocked by 2-quinoxaline-carboxamide-N-adamantan-1-yl (NPS 2390), (3aS,6aS)-6a-naphtalan-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c] furan-1-on (BAY 36-7620), and 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate Et ester (CPCCOEt), but was not displaced by competitive mGlu1 receptor ligands such as glutamate and quisqualate, suggesting that R214127, NPS 2390, BAY 36-7620, and CPCCOEt bind to the same site or mutually exclusive sites. Experiments using rat cortex, striatum, hippocampus and cerebellum revealed that [³H]R214127 labeled a single high-affinity binding site (K_D ∼ 1 nM). B_max values were highest in the cerebellum (4302 fmol/mg of protein) and were 741, 688, and 471 fmol/mg of protein in the striatum, hippocampus, and cortex, resp. The distribution of [³H]R214127 binding in rat brain was investigated in more detail by radioligand autoradiog. A high d. of binding sites was detected in the mol. layer of the cerebellum. Moderate labeling was seen in the CA3 and dentate gyrus of the hippocampus, thalamus, olfactory tubercle, amygdala, and substantia nigra reticulata. The cerebral cortex, caudate putamen, ventral pallidum, and nucleus accumbens showed lower labeling. The high affinity and selectivity of [³H]R214127 for mGlu1 receptors renders this compound the ligand of choice to study the native mGlu1 receptor in brain.

Molecular Pharmacology published new progress about 226878-01-9. 226878-01-9 belongs to quinoxaline, auxiliary class Neuronal Signaling,mGluR, name is N-(Adamantan-1-yl)quinoxaline-2-carboxamide, and the molecular formula is C19H21N3O, SDS of cas: 226878-01-9.

Referemce:
https://en.wikipedia.org/wiki/Quinoxaline,
Quinoxaline | C8H6N2 | ChemSpider

Kim, Eunwoo published the artcilePharmacokinetic comparison between tablet of varenicline tartrate and orally disintegrating film of varenicline salicylate in healthy subjects, Related Products of quinoxaline, the publication is International Journal of Clinical Pharmacology and Therapeutics (2021), 59(6), 478-484, database is CAplus and MEDLINE.

Varenicline is an efficacious aid for smoking cessation. In this study, the pharmacokinetics and safety were compared between film-coated tablets of varenicline tartrate (reference drug) and the newly developed orally disintegrating films of varenicline salicylate (test drug), both of them contained 1 mg of varenicline. A randomized, open-label, single-dose, two-sequence, two-period crossover study was conducted in healthy male subjects. Serial blood samples were obtained for up to 72 h in each period, with a washout period of 7 days or more. The pharmacokinetic parameters were calculated using the noncompartmental method. Safety profiles were assessed throughout the study. A total of 28 subjects completed the study. The plasma varenicline concentration-time profiles were similar for the two study drugs. The maximum plasma varenicline concentration (Cmax) was 5,768.95 ng/L (mean) and 5,780.55 ng/L for the test drug and reference drug, resp. The areas under the concentration-time curve from time 0 to the last measurable time point (AUC0 – t) were 94,086.30 h x ng/L and 89,958.55 h x ng/L for the test drug and reference drug, resp. The geometric mean ratios (90% confidence intervals) of the test drug to the reference drug for Cmax and AUC0 – t were 0.9955 (0.9488 – 1.0444) and 1.0449 (0.9848 – 1.1088), resp., which fell within the bioequivalence range of 0.8 – 1.25. There was no difference in safety between the study drugs. The pharmacokinetics and safety profiles were similar between the two study drugs. The orally disintegrating film of varenicline salicylate can be an alternative to varenicline tartrate tablets.

International Journal of Clinical Pharmacology and Therapeutics published new progress about 375815-87-5. 375815-87-5 belongs to quinoxaline, auxiliary class Neuronal Signaling,AChR,Natural product, name is 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate, and the molecular formula is C17H19N3O6, Related Products of quinoxaline.

Referemce:
https://en.wikipedia.org/wiki/Quinoxaline,
Quinoxaline | C8H6N2 | ChemSpider

Murphy, Brendan J. published the artcileVarenicline L-tartrate crystal forms: Characterization through crystallography, spectroscopy, and thermodynamics, SDS of cas: 375815-87-5, the publication is Journal of Pharmaceutical Sciences (2010), 99(6), 2766-2776, database is CAplus and MEDLINE.

This research utilized crystallog., spectroscopic, and thermal anal. data to assess the thermodn. stability relationship between the three known crystal forms of Varenicline L-tartrate. Of the two anhydrous forms (Forms A and B), Form B was determined to be the stable form at 0 K based on its calculated true d., hydrogen bonding in the crystal lattice, and application of the IR rule. Form A has a higher m.p. and higher solubility at room temperature as compared to Form B, indicating that these forms are enantiotropically related. Application of the eutectic-melting method enabled accurate determination of the transition temperature (63°), with Form B as the stable anhydrous form at room temperature The stability relationships between the anhydrous polymorphs and the monohydrate (Form C) were assessed through exposure of the anhydrous forms to a range of water vapor pressures at room temperature A phase boundary was identified, with the monohydrate being the thermodynamically stable form above critical water activity values of 0.85 and 0.94 for Forms A and B, resp. These results provide a better understanding of the form stability as it relates to normal manufacturing and storage conditions for the active pharmaceutical ingredient and drug product. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2766-2776, 2010.

Journal of Pharmaceutical Sciences published new progress about 375815-87-5. 375815-87-5 belongs to quinoxaline, auxiliary class Neuronal Signaling,AChR,Natural product, name is 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate, and the molecular formula is C17H19N3O6, SDS of cas: 375815-87-5.

Referemce:
https://en.wikipedia.org/wiki/Quinoxaline,
Quinoxaline | C8H6N2 | ChemSpider

Kurosawa, Toshiki published the artcileInvolvement of Proton-Coupled Organic Cation Antiporter in Varenicline Transport at Blood-Brain Barrier of Rats and in Human Brain Capillary Endothelial Cells, Application of 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate, the publication is Journal of Pharmaceutical Sciences (2017), 106(9), 2576-2582, database is CAplus and MEDLINE.

Varenicline is a selective partial α₄β₂ nicotinic acetylcholine receptor agonist, which is used to help achieve smoking cessation. Here, we investigated varenicline transport at the blood-brain barrier by means of in vivo microdialysis, in situ brain perfusion, and brain efflux index measurements in rats, and in vitro uptake studies in human brain capillary endothelial cells. Microdialysis demonstrated that varenicline is actively transported from blood to brain in rats. Blood-to-brain uptake transport of varenicline, as measured by the in situ brain perfusion technique, was strongly inhibited by diphenhydramine, a potent inhibitor of proton-coupled organic cation (H⁺/OC) antiporter. However, brain efflux index study showed that brain-to-blood efflux transport of varenicline was not inhibited by diphenhydramine. In human brain capillary endothelial cells, varenicline was taken up time- and concentration-dependently. The uptake was dependent on an oppositely directed proton gradient, but was independent of extracellular sodium and membrane potential. The uptake was inhibited by a metabolic inhibitor, and by substrates of H⁺/OC antiporter, but not by substrates or inhibitors of OCTs, OCTNs, PMAT, and MATE1, which are known organic cation transporters. The present results suggest that the H⁺/OC antiporter contributes predominantly to varenicline uptake at the blood-brain barrier.

Journal of Pharmaceutical Sciences published new progress about 375815-87-5. 375815-87-5 belongs to quinoxaline, auxiliary class Neuronal Signaling,AChR,Natural product, name is 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate, and the molecular formula is C17H19N3O6, Application of 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate.

Referemce:
https://en.wikipedia.org/wiki/Quinoxaline,
Quinoxaline | C8H6N2 | ChemSpider

Rollema, Hans published the artcilePreclinical pharmacology of the α4β2 nAChR partial agonist varenicline related to effects on reward, mood and cognition, Related Products of quinoxaline, the publication is Biochemical Pharmacology (2009), 78(7), 813-824, database is CAplus and MEDLINE.

The pharmacol. properties and pharmacokinetic profile of the α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline provide an advantageous combination of free brain levels and functional potencies at the target receptor that for a large part explain its efficacy as a smoking cessation aid. Since α4β2 and other nAChR subtypes play important roles in mediating central processes that control reward, mood, cognition and attention, there is interest in examining the effects of selective nAChR ligands such as varenicline in preclin. animal models that assess these behaviors. Here we describe results from studies on varenicline’s effects in animal models of addiction, depression, cognition and attention and discuss these in the context of recently published preclin. and preliminary clin. studies that collected data on varenicline’s effects on mood, cognition and alc. abuse disorder. Taken together, the preclin. and the limited clin. data show beneficial effects of varenicline, but further clin. studies are needed to evaluate whether the preclin. effects observed in animal models are translatable to the clinic.

Biochemical Pharmacology published new progress about 375815-87-5. 375815-87-5 belongs to quinoxaline, auxiliary class Neuronal Signaling,AChR,Natural product, name is 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate, and the molecular formula is C17H19N3O6, Related Products of quinoxaline.

Referemce:
https://en.wikipedia.org/wiki/Quinoxaline,
Quinoxaline | C8H6N2 | ChemSpider

Rollema, Hans published the artcileVarenicline has antidepressant-like activity in the forced swim test and augments sertraline’s effect, SDS of cas: 375815-87-5, the publication is European Journal of Pharmacology (2009), 605(1-3), 114-116, database is CAplus and MEDLINE.

Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist developed as a smoking cessation aid, showed antidepressant-like activity in the forced swim test in two mouse strains. In addition, a low varenicline dose significantly enhanced the effects of moderately active doses of the selective serotonin reuptake inhibitor sertraline. These findings are consistent with the notion that reducing α4β2 nicotinic acetylcholine receptor activity either by antagonists or by partial agonists that can partially activate or desensitize acetylcholine receptors is associated with antidepressant-like properties. These data suggest that varenicline may have antidepressant potential and can, when combined, augment antidepressant responses of selective serotonin reuptake inhibitors.

European Journal of Pharmacology published new progress about 375815-87-5. 375815-87-5 belongs to quinoxaline, auxiliary class Neuronal Signaling,AChR,Natural product, name is 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate, and the molecular formula is C17H19N3O6, SDS of cas: 375815-87-5.

Referemce:
https://en.wikipedia.org/wiki/Quinoxaline,
Quinoxaline | C8H6N2 | ChemSpider

Brunner, Joseph I. published the artcilePharmacological Validation of Candidate Causal Sleep Genes Identified in an N2 Cross, COA of Formula: C17H19N3O6, the publication is Journal of Neurogenetics (2011), 25(4), 167-181, database is CAplus and MEDLINE.

Despite the substantial impact of sleep disturbances on human health and the many years of study dedicated to understanding sleep pathologies, the underlying genetic mechanisms that govern sleep and wake largely remain unknown. Recently, the authors completed large-scale genetic and gene expression analyses in a segregating inbred mouse cross and identified candidate causal genes that regulate the mammalian sleep-wake cycle, across multiple traits including total sleep time, amounts of rapid eye movement (REM), non-REM, sleep bout duration, and sleep fragmentation. Here the authors describe a novel approach toward validating candidate causal genes, while also identifying potential targets for sleep-related indications. Select small-mol. antagonists and agonists were used to interrogate candidate causal gene function in rodent sleep polysomnog. assays to determine impact on overall sleep architecture and to evaluate alignment with associated sleep-wake traits. Significant effects on sleep architecture were observed in validation studies using compounds targeting the muscarinic acetylcholine receptor M3 subunit (Chrm3) (wake promotion), nicotinic acetylcholine receptor alpha4 subunit (Chrna4) (wake promotion), dopamine receptor D5 subunit (Drd5) (sleep induction), serotonin 1D receptor (Htr1d) (altered REM fragmentation), glucagon-like peptide-1 receptor (Glp1r) (light sleep promotion and reduction of deep sleep), and calcium channel, voltage-dependent, T type, alpha 1I subunit (Cacna1i) (increased bout duration of slow wave sleep). Taken together, these results show the complexity of genetic components that regulate sleep-wake traits and highlight the importance of evaluating this complex behavior at a systems level. Pharmacol. validation of genetically identified putative targets provides a rapid alternative to generating knock out or transgenic animal models, and may ultimately lead towards new therapeutic opportunities.

Journal of Neurogenetics published new progress about 375815-87-5. 375815-87-5 belongs to quinoxaline, auxiliary class Neuronal Signaling,AChR,Natural product, name is 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate, and the molecular formula is C17H19N3O6, COA of Formula: C17H19N3O6.

Referemce:
https://en.wikipedia.org/wiki/Quinoxaline,
Quinoxaline | C8H6N2 | ChemSpider