Heterocyclic Building Blocks-quinoxaline

Yanamala, Naveena published the artcilePreferential binding of allosteric modulators to active and inactive conformational states of metabotropic glutamate receptors, Category: quinoxaline, the publication is BMC Bioinformatics (2008), No pp. given, database is CAplus and MEDLINE.

Metabotropic glutamate receptors (mGluRs) are G protein coupled receptors that play important roles in synaptic plasticity and other neuro-physiol. and pathol. processes. Allosteric mGluR ligands are particularly promising drug targets because of their modulatory effects – enhancing or suppressing the response of mGluRs to glutamate. The mechanism by which this modulation occurs is not known. Here, the authors propose the hypothesis that pos. and neg. modulators will differentially stabilize the active and inactive conformations of the receptors, resp. To test this hypothesis, the authors have generated computational models of the transmembrane regions of different mGluR subtypes in two different conformations. The inactive conformation was modeled using the crystal structure of the inactive, dark state of rhodopsin as template and the active conformation was created based on a recent model of the light-activated state of rhodopsin. Ligands for which the nature of their allosteric effects on mGluRs is exptl. known were docked to the modeled mGluR structures using ArgusLab and Autodock softwares. The authors find that the allosteric ligand binding pockets of mGluRs are overlapping with the retinal binding pocket of rhodopsin, and that ligands have strong preferences for the active and inactive states depending on their modulatory nature. In 8 out of 14 cases (57%), the neg. modulators bound the inactive conformations with significant preference using both docking programs, and 6 out of 9 cases (67%), the pos. modulators bound the active conformations. Considering results by the individual programs only, even higher correlations were observed: 12/14 (86%) and 8/9 (89%) for ArgusLab and 10/14 (71%) and 7/9 (78%) for AutoDock. These findings strongly support the hypothesis that mGluR allosteric modulation occurs via stabilization of different conformations analogous to those identified in rhodopsin where they are induced by photochem. isomerization of the retinal ligand – despite the extensive differences in sequences between mGluRs and rhodopsin.

BMC Bioinformatics 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 C38H74Cl2N2O4, Category: quinoxaline.

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

Hong, L. Elliot published the artcileEffects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder, Application In Synthesis of 375815-87-5, the publication is Archives of General Psychiatry (2011), 68(12), 1195-1206, database is CAplus and MEDLINE.

The administration of nicotine transiently improves many neurobiol. and cognitive functions in schizophrenia and schizoaffective disorder. It is not yet clear which nicotinic acetylcholine receptor (nAChR) subtype or subtypes are responsible for these seemingly pervasive nicotinic effects in schizophrenia and schizoaffective disorder. Because α4β2 is a key nAChR subtype for nicotinic actions, we investigated the effect of varenicline tartrate, a relatively specific α4β2 partial agonist and antagonist, on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans. A double-blind, parallel, randomized, placebo-controlled trial of patients with schizophrenia or schizoaffective disorder was conducted to examine the effects of varenicline on biomarkers at 2 wk (short-term treatment) and 8 wk (long-term treatment), using a slow titration and moderate dosing strategy for retaining α4β2-specific effects while minimizing adverse effects. Participants included a total of 69 smoking and nonsmoking patients; 64 patients completed week 2, and 59 patients completed week 8. Main outcome measures were prepulse inhibition, sensory gating, antisaccade, spatial working memory, eye tracking, processing speed, and sustained attention. Results: A moderate dose of varenicline (1) significantly reduced the P50 sensory gating deficit in nonsmokers after long-term treatment (P=.006), (2) reduced startle reactivity (P=.02) regardless of baseline smoking status, and (3) improved executive function by reducing the antisaccadic error rate (P=.03) regardless of smoking status. A moderate dose of varenicline had no significant effect on spatial working memory, predictive and maintenance pursuit measures, processing speed, or sustained attention by Conners’ Continuous Performance Test. Clin., there was no evidence of exacerbation of psychiatric symptoms, psychosis, depression, or suicidality using a gradual titration (1-mg daily dose). Moderate-dose treatment with varenicline has a unique treatment profile on core schizophrenia-related biomarkers. Further development is warranted for specific nAChR compounds and dosing and duration strategies to target subgroups of schizophrenic patients with specific biol. deficits. Trial Registration: clinicaltrials.gov Identifier: NCT00492349.

Archives of General Psychiatry 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 In Synthesis of 375815-87-5.

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

Lu, Yuting published the artcileImpurity profiling of varenicline tartrate by LC-QTOF mass spectrometric techniques during drug development, Product Details of C17H19N3O6, the publication is Journal of Pharmaceutical and Biomedical Analysis (2018), 306-313, database is CAplus and MEDLINE.

HPLC-QTOF-MS method was developed for the separation and characterization of related substances in varenicline tartrate drug material. The separation used InertSustain C18 column (4.6 × 150 mm, 5 μm) with liner gradient elution using 0.05% trifluoroacetic acid as mobile phase A and acetonitrile as mobile phase B. The degradation studies were conducted under the ICH prescribed stress conditions. Varenicline tartrate was unstable to alk., oxidative, thermal and photolytic stresses, but relatively stable under acid stress condition. Thirteen related substances were found in varenicline tartrate and its stressed samples. Their structures were identified mainly through pos. ESI high resolution QTOF mass spectrometric anal. of the parent and product ion accurate masses and the calculated elemental compositions Among the 13 substances, 7 were process-related and 6 were degradation products, and two of them were further verified by chem. synthesis and NMR spectroscopic determination Their formation mechanisms are discussed, and the key steps in the manufacturing processes are determined to provide varenicline tartrate with high purity.

Journal of Pharmaceutical and Biomedical Analysis 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, Product Details of C17H19N3O6.

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

Ding, Li published the artcileSmoking-cessation drugs and the related technological progress, Quality Control of 375815-87-5, the publication is Shanghai Yiyao (2007), 28(4), 170-172, database is CAplus.

A review. At present, smoking has been a serious social problem. Smoking-cessation drugs and the related technol. are developing in a variety of directions. The development of nicotine replacement therapy and technol., chem. drugs (amfebutamone hydrochloride, varenicline tartrate and rimonabant), vaccine, tradition Chinese medicines, and acupuncture therapy are reviewed with 3 references

Shanghai Yiyao 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, Quality Control of 375815-87-5.

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

Wildeboer-Andrud, Kristin M. published the artcileThe smoking cessation drug varenicline improves deficient P20-N40 inhibition in DBA/2 mice, Related Products of quinoxaline, the publication is Pharmacology, Biochemistry and Behavior (2011), 100(1), 17-24, database is CAplus and MEDLINE.

Varenicline, an FDA approved smoking cessation pharmacotherapy, is an α4β2* nicotinic acetylcholine receptor (nAChR) partial agonist and an α7* nAChR full agonist. Both subtypes of nAChR are involved in modulating auditory evoked responses in rodents. In DBA/2 mice, an inbred strain, auditory evoked responses to paired auditory stimuli fail to inhibit to the second stimulus. This mouse strain replicates the auditory evoked response inhibition deficit experienced by the majority of schizophrenia patients. In this current study, we examined the effects of five different doses of varenicline (0.06, 0.3, 0.6, 3 and 6 mg/kg) on auditory evoked responses in anesthetized DBA/2 mice. We also administered α4β2* and α7* nAChR selective antagonists prior to varenicline administration to determine which nAChR subtypes mediate the effects of varenicline. Four of the five doses of varenicline produced improvements in auditory evoked response inhibition deficits. Selective blockade of either the α4β2* or α7* nAChR in competition with 0.6 mg/kg varenicline prevented varenicline induced improvements. In competition with a higher dose of varenicline (3 mg/kg) only blockade of the α4β2* nAChR prevented varenicline induced improvement in auditory evoked response inhibition. These data indicate the importance of α4β2* nAChRs and the potential involvement of the α7* subtype in varenicline’s effects on auditory evoked responses in DBA/2 mice.

Pharmacology, Biochemistry and Behavior 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 C7H16Cl2Si, Related Products of quinoxaline.

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

Xue, Zhaoliang published the artcileCalcium-sensing receptor antagonist NPS2390 attenuates neuronal apoptosis though intrinsic pathway following traumatic brain injury in rats, SDS of cas: 226878-01-9, the publication is Biochemical and Biophysical Research Communications (2017), 486(2), 589-594, database is CAplus and MEDLINE.

Traumatic brain injury (TBI) initiates a complex cascade of neurochem. and signaling changes that leads to neuronal apoptosis, which contributes to poor outcomes for patients with TBI. Previous study indicates that calcium-sensing receptor (CaSR) activation contributes to neuron death in focal cerebral ischemia-reperfusion mice, however, its role in neuronal apoptosis after TBI is not well-established. Using a controlled cortical impact model in rats, the present study was designed to determine the effect of CaSR inhibitor NPS2390 upon neuronal apoptosis after TBI. Rats were randomly distributed into three groups undergoing the sham surgery or TBI procedure, and NPS2390 (1.5 mg/kg) was infused s.c. at 30 min and 120 min after TBI. All rats were sacrificed at 24 h after TBI. Our data indicated that NPS2390 significantly reduced the brain edema and improved the neurol. function after TBI. In addition, NPS2390 decreased caspase-3 levels and the number of apoptotic neurons. Furthermore, NPS2390 up-regulated anti-apoptotic protein Bcl-2 expression and down-regulated pro-apoptotic protein Bax, and reduced subsequent release of cytochrome c into the cytosol. In summary, this study indicated that inhibition of CaSR by NPS2390 attenuates neuronal apoptosis after TBI, in part, through modulating intrinsic apoptotic pathway.

Biochemical and Biophysical Research Communications 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 C15H14O, SDS of cas: 226878-01-9.

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

Carson, Kristin Veronica published the artcileSafety of varenicline tartrate and counseling versus counseling alone for smoking cessation: a randomized controlled trial for inpatients (STOP study), Computed Properties of 375815-87-5, the publication is Nicotine & Tobacco Research (2014), 16(11), 1495-1502, database is CAplus and MEDLINE.

Introduction: Inpatient medical settings offer an opportunistic environment for initiating smoking cessation interventions to patients reflecting on their health. Current evidence has shown the superior efficacy of varenicline tartrate (VT) for smoking cessation compared with other tobacco cessation therapies; however, recent evidence also has highlighted concerns about the safety and tolerability of VT. Given these apprehensions, we aimed to evaluate the safety and effectiveness of VT plus quitline counseling compared to quitline-counseling alone in the inpatient medical setting. Methods: Adult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to 3 hospitals were randomized to receive either 12 wk of varenicline tartrate (titrated from 0.5 mg daily to 1 mg twice daily) plus quitline-counseling (VT+C), (n = 196) or quitline-counseling alone (n = 196). Results: VT was well tolerated in the inpatient setting among subjects admitted with acute smoking-related illnesses (mean age 52.8 ± 2.89 and 53.7 ± 2.77 years in the VT+C and counseling alone groups, resp.). The most common self-reported adverse event during the 12-wk treatment phase was nausea (16.3% in the VT+C group compared with 1.5% in the counseling alone group). Thirteen deaths occurred during the study period (n = 6 were in the VT+C arm compared with n = 7 in the counseling alone arm). All of these subjects had known comorbidities or developed underlying comorbidities. Conclusions: VT appears to be a safe and well-tolerated opportunistic treatment for inpatient smokers who have related chronic disease. Based on the proven efficacy of varenicline from outpatient studies and our recent inpatient evidence, we suggest it be considered as part of standard care in the hospital setting.

Nicotine & Tobacco Research 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, Computed Properties of 375815-87-5.

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

Goekce, Basak published the artcileAssociation of human serum paraoxonase-1 with some respiratory drugs, Name: 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline (2R,3R)-2,3-dihydroxysuccinate, the publication is Journal of Biochemical and Molecular Toxicology (2019), 33(12), e22407, database is CAplus and MEDLINE.

In this study, we investigated the effects of certain respiratory drugs, which are mainly used on human serum paraoxonase-1 (hPON1; EC 3.1.8.1). hPON1 was purified from human serum, with 354.91 fold and 45% yield by using two simple step procedures including, first, ammonium sulfate precipitation, then, Sepharose-4B-L-tyrosine-1-naphthylamine hydrophobic interaction chromatog. SDS-polyacrylamide gel electrophoresis showed a single protein band belonging to hPON1 with 43 kDa. All the pharmaceutical compounds inhibited the PON1 enzyme highly at the micromolar level. The obtained IC₅₀ values for nine different pharmaceutics ranged from 0.219μM (salbutamol sulfate) to 67.205μM (montelukast sodium). So, all drugs could be considered as potent hPON1 inhibitors. K_i values and inhibition types were determined by Lineweaver-Burk graphs. While varenicline tartrate and moxifloxacin hydrochloride inhibited the enzyme in a noncompetitive manner, others inhibited it in a mixed manner.

Journal of Biochemical and Molecular Toxicology 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, Name: 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

Wouda, Jelte A. published the artcileVarenicline attenuates cue-induced relapse to alcohol, but not nicotine seeking, while reducing inhibitory response control, SDS of cas: 375815-87-5, the publication is Psychopharmacology (Heidelberg, Germany) (2011), 216(2), 267-277, database is CAplus and MEDLINE.

Rationale: Treatment of the most widely abused drugs, nicotine and alc., is hampered by high rates of relapse. Varenicline tartrate, an α4β2 nicotinic receptor partial agonist, is currently prescribed as a smoking cessation aid. However, there is emerging evidence that it may also modulate alc. seeking and cognitive functioning in rats. Objectives: As preclin. data on alc. taking and relapse are limited, we used a self-administration-reinstatement model to evaluate the effects of varenicline on operant responding for alc. (12%, volume/volume), i.v. nicotine (40 μg/kg/inf.), sucrose (10%, w/v) and on cue-induced relapse to alc. and nicotine seeking in rats. At the cognitive level, we assed varenicline’s effects on 5-choice serial reaction time task (5-CSRTT) performance with a focus on correct responses (attention) and premature responding (impulsivity), modalities that have previously been associated with addictive behavior. Results: Varenicline, at doses of 1.5 and 2.5 mg/kg, reduced alc. and nicotine self-administration and enhanced operant responding for sucrose. At these doses, varenicline reduced cue-induced relapse to alc., but not nicotine seeking. In contrast, at 0.5 mg/kg, varenicline facilitated cue-induced nicotine seeking. Similar to nicotine, varenicline increased premature responding at low doses, but had no effect on any of the other behavioral parameters in the 5-CSRTT. Conclusions: Our data indicate that varenicline specifically reduced responding for nicotine and alc., but not for natural reinforcers such as sucrose. Interestingly, varenicline strongly attenuated cue-induced relapse to alc. seeking, but not nicotine seeking. Varenicline may therefore be a promising aid in the treatment of alc. addiction.

Psychopharmacology (Heidelberg, Germany) 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 C3H9ClOS, SDS of cas: 375815-87-5.

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

Huang, Shuaishuai published the artcileTranscription factor CREB is involved in CaSR-mediated cytoskeleton gene expression, Recommanded Product: N-(Adamantan-1-yl)quinoxaline-2-carboxamide, the publication is Anatomical Record (2015), 298(3), 501-512, database is CAplus and MEDLINE.

Our previous studies illustrated that a steady increase of intracellular calcium concentration ([Ca²⁺]i) was important for maintaining microtubules (MTs) rearrangement in apoptotic cells. However, little is known about the effect of calcium sensing receptor (CaSR)-mediated increase in [Ca²⁺]i on cytoskeleton gene expression. We examined the impact of taxol or CaSR agonist/antagonist on the regulation of [Ca²⁺]i concentration, cytoskeleton arrangement, phosphorylated CREB and cytoskeleton gene expressions in HeLa cells with dominant neg. plasmid of CREB (PM). This study demonstrated that Gdcl3 (a specific CaSR agonist) evoked a rapid increase of [Ca²⁺]i, formed a rigid bundle of MTs which surrounded the nucleus and decreased the cytoskeleton gene expressions in HeLa cells. These effects were rescued by addition of NPS2390 (a specific CaSR antagonist). Moreover, CaSR activity affected cytoskeleton gene expression through transcription factor CREB. Histoscores of pCREB immunoreactivity in tissues of cervical adenocarcinoma, renal clear cell carcinoma, and diffuse large B-cell lymphoma were markedly increased compared with non malignant tissue. These data demonstrate, for the first time, that CaSR-mediated increase in [Ca²⁺]i probably modulate cytoskeleton organization and gene expression via transcription factor CREB. Anat Rec, 298:501-512, 2015. © 2014 Wiley Periodicals, Inc.

Anatomical Record 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, Recommanded Product: N-(Adamantan-1-yl)quinoxaline-2-carboxamide.

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