Tag: M.W=500-550

Pinna, Annalisa published the artcileAntidyskinetic effect of A_2A and 5HT_1A/1B receptor ligands in two animal models of Parkinson’s disease, Application of 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, the publication is Movement Disorders (2016), 31(4), 501-511, database is CAplus and MEDLINE.

Background : The serotonin 5-HT_1A/1B receptor agonist eltoprazine suppressed dyskinetic-like behavior in animal models of Parkinson’s disease (PD) but simultaneously reduced levodopa (L-dopa)-induced motility. Moreover, adenosine A_2A receptor antagonists, such as preladenant, significantly increased L-dopa efficacy in PD without exacerbating dyskinetic-like behavior. Objectives : We evaluated whether a combination of eltoprazine and preladenant may prevent or suppress L-dopa-induced dyskinesia, without impairing L-dopa’s efficacy in relieving motor signs, in 2 PD models: unilateral 6-hydroxydopamine-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Methods : Rotational behavior and abnormal involuntary movements, or disability and L-dopa-induced dyskinesia were evaluated in 6-hydroxydopamine-lesioned rats and MPTP-treated monkeys, resp. Moreover, in the rodent striatum, induction of immediate-early gene zif-268, an index of long-term changes, was correlated with dyskinesia. Results : In 6-hydroxydopamine-lesioned rats, combined administration of L-dopa (4 mg/kg) plus eltoprazine (0.6 mg/kg) plus preladenant (0.3 mg/kg) significantly prevented or reduced dyskinetic-like behavior without impairing motor activity. Zif-268 was increased in the striatum of rats treated with L-dopa and L-dopa plus preladenant compared with vehicle. In contrast, rats treated with eltoprazine (with or without preladenant) had lower zif-268 activation after chronic treatment in both the dyskinetic and L-dopa-non-primed groups. Moreover, acute L-dopa plus eltoprazine plus preladenant prevented worsening of motor performance (adjusting step) and sensorimotor integration deficit. Similar results were obtained in MPTP-treated monkeys, where a combination of preladenant with eltoprazine was found to counteract dyskinesia and maintain the full therapeutic effects of a low dose of L-dopa. Conclusions : Our results suggest a promising nondopaminergic pharmacol. strategy for the treatment of dyskinesia in PD. cpr 2016 International Parkinson and Movement Disorder Society.

Movement Disorders published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C25H29N9O3, Application of 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Claff, Tobias published the artcileSingle Stabilizing Point Mutation Enables High-Resolution Co-Crystal Structures of the Adenosine A_2A Receptor with Preladenant Conjugates, Computed Properties of 377727-87-2, the publication is Angewandte Chemie, International Edition (2022), 61(22), e202115545, database is CAplus and MEDLINE.

The G protein-coupled adenosine A_2A receptor (A_2AAR) is an important new (potential) drug target in immuno-oncol., and for neurodegenerative diseases. Preladenant and its derivatives belong to the most potent A_2AAR antagonists displaying exceptional selectivity. While crystal structures of the human A_2AAR have been solved, mostly using the A_2A-StaR2 protein that bears 9 point mutations, co-crystallization with Preladenant derivatives has so far been elusive. We developed a new A_2AAR construct harboring a single point mutation (S91^3.39K) which renders it extremely thermostable. This allowed the co-crystallization of two novel Preladenant derivatives, the polyethylene glycol-conjugated (PEGylated) PSB-2113, and the fluorophore-labeled PSB-2115. The obtained crystal structures (2.25 S and 2.6 S resolution) provide explanations for the high potency and selectivity of Preladenant derivatives They represent the first crystal structures of a GPCR in complex with PEG- and fluorophore-conjugated ligands. The applied strategy is predicted to be applicable to further class A GPCRs.

Angewandte Chemie, International Edition published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C25H29N9O3, Computed Properties of 377727-87-2.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Comeo, Eleonora published the artcileSubtype-Selective Fluorescent Ligands as Pharmacological Research Tools for the Human Adenosine A_2A Receptor, Computed Properties of 377727-87-2, the publication is Journal of Medicinal Chemistry (2020), 63(5), 2656-2672, database is CAplus and MEDLINE.

Among class A G protein-coupled receptors (GPCR), the human adenosine A_2A receptor (hA_2AAR) remains an attractive drug target. However, translation of A_2AAR ligands into the clinic has proved challenging and an improved understanding of A_2AAR pharmacol. could promote development of more efficacious therapies. Subtype-selective fluorescent probes would allow detailed real-time pharmacol. investigations both in vitro and in vivo. In the present study, two families of fluorescent probes were designed around the known hA_2AAR selective antagonist preladenant (SCH 420814). Both families of fluorescent antagonists retained affinity at the hA_2AAR, selectivity over all other adenosine receptor subtypes and allowed clear visualization of specific receptor localization through confocal imaging. Furthermore, the Alexa Fluor 647-labeled conjugate allowed measurement of ligand binding affinities of unlabeled hA_2AAR antagonists using a bioluminescence resonance energy transfer (NanoBRET) assay. The fluorescent ligands developed here can therefore be applied to a range of fluorescence-based techniques to further interrogate hA_2AAR pharmacol. and signaling.

Journal of Medicinal Chemistry published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C25H29N9O3, Computed Properties of 377727-87-2.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Szaboo, Nikoletta published the artcileNovel therapy in Parkinson’s disease: adenosine A_2A receptor antagonists, HPLC of Formula: 377727-87-2, the publication is Expert Opinion on Drug Metabolism & Toxicology (2011), 7(4), 441-455, database is CAplus and MEDLINE.

A review. Introduction: Parkinson’s disease (PD) is a progressive neurodegenerative disorder. To date, most of the currently available therapies in PD target the dopaminergic system and none of these therapeutic approaches have been proven to modify the course of the disease. To various extents, these drugs can also cause motor and non-motor complications. A novel target, the adenosine A_2A receptor (AA2AR), was recently identified, blockade of which may alleviate Parkinsonian symptoms, reduce motor fluctuations and potentially afford neuroprotection. Areas covered: This review is based on a PubMed search covering the relationship of the adenosine receptors and PD. The role of the AA2AR is reviewed and the results of preclin. investigations of antagonists are assessed. A synopsis of current drug development is provided, with a special focus on the pharmacokinetics and relevant clin. trials. Expert opinion: The localization of the AA2AR in the central nervous system, the ultra structural localization and the mol. mechanism of its action reveal the potential importance of the AA2AR in movement disorders. The theor. background and exptl. data indicate that AA2AR antagonists may have a potential therapeutic effect in Parkinson’s disease. More importantly, the putative neuroprotective effect needs further investigation.

Expert Opinion on Drug Metabolism & Toxicology published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C8H6ClF3, HPLC of Formula: 377727-87-2.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Zhou, Xiaoyun published the artcileIn vivo evaluation of [11C]preladenant positron emission tomography for quantification of adenosine A2A receptors in the rat brain, Safety of 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, the publication is Journal of Cerebral Blood Flow & Metabolism (2017), 37(2), 577-589, database is CAplus and MEDLINE.

[11C]Preladenant was developed as a novel adenosine A2A receptor positron emission tomog. radioligand. The present study aims to evaluate the suitability of [11C]preladenant positron emission tomog. for the quantification of striatal A2A receptor d. and the assessment of striatal A2A receptor occupancy by KW-6002. Tracer kinetics was quantified by the two-tissue compartment model, Logan graphical anal. and several reference tissue-based models. Test-retest reproducibility was assessed by repeated imaging on two consecutive days. Two-tissue compartment model and Logan plot estimated comparable distribution volume (VT) values of ∼10 in the A2A receptor-rich striatum and substantially lower values in all extra-striatal regions (∼1.5-2.5). The simplified reference tissue model with midbrain or occipital cortex as the reference region proved to be the best non-invasive model for quantification of A2A receptor, showing a striatal binding potential (BPND) value of ∼5.5, and a test-retest variability of ∼5.5%. The brain metabolite anal. showed that at 60-min post injection, 17% of the radioactivity in the brain was due to radioactive metabolites. The ED50 of KW-6002 in rat striatum for i.p. injection was 0.044-0.062 mg/kg. The study demonstrates that [11C]preladenant is a suitable tracer to quantify striatal A2A receptor d. and assess A2A receptor occupancy by A2A receptor-targeting mols.

Journal of Cerebral Blood Flow & Metabolism published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C10H10O2, Safety of 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Sakata, Muneyuki published the artcileInitial evaluation of an adenosine A2A receptor ligand, 11C-preladenant, in healthy human subjects, HPLC of Formula: 377727-87-2, the publication is Journal of Nuclear Medicine (2017), 58(9), 1464-1470, database is CAplus and MEDLINE.

11C-preladenant is a selective antagonist for mapping of cerebral adenosine A2A receptors (A2ARs) by PET. This is a first-in-human study to examine the safety, radiation dosimetry, and brain imaging of 11C-preladenant in healthy human subjects. Dynamic 11C-preladenant PET scans (90 min) were obtained in 5 healthy male subjects. During the scan, arterial blood was sampled at various time intervals, and the fraction of the parent compound in plasma was determined For anat. coregistration, T1-weighted MRI was performed. The total distribution volume (VT) was estimated using 1- and 2-tissue-compartment models (1T and 2T, resp.). The distribution volume ratio (DVR) was calculated from VT of target and reference region and obtained with a noninvasive Logan graphical reference tissue method (t* = 30 min). The applicability of a shortened protocol as an alternative to the 90-min PET scan was investigated. Tracer biodistribution and dosimetry were determined in 3 healthy male subjects, using serial whole-body PET scans acquired over 2 h after 11C-preladenant injection. There were no serious adverse events in any of the subjects throughout the study period. 11C-preladenat readily entered the brain, with a peak uptake in the putamen and head of the caudate nucleus 30-40 min after tracer injection. Other brain regions showed rapid clearance of radioactivity. The regional distribution of 11C-preladenant was consistent with known A2AR densities in the brain. At pseudoequil. (reached at 40 min after injection), stable target-to-cerebellar cortex ratios of around 3.8-10.0 were obtained. The 2T fit better than the 1T in the low-d. A2AR regions. In contrast, there were no significant differences between 1T and 2T in the high-A2AR-d. regions. DVRs in the putamen and head of the caudate nucleus were around 3.8-10.3 when estimated using a Logan graphical reference tissue method with cerebellum as the reference region. PET scanning at 50 or 70 min can provide the stable DVR estimates within 10% or 5% differences at most, resp. The radioactivity was mainly excreted through the hepatobiliary system after 11C-preladenant injection. As a result, the absorbed dose (μy/MBq) was highest in the gallbladder wall (mean ± SD, 17.0 ± 2.5) and liver (11.7 ± 2.1). The estimated ED for 11C-preladenant was 3.7 ± 0.4 μSv/MBq. This initial evaluation indicated that 11C-preladenat is suitable for imaging of A2ARs in the brain.

Journal of Nuclear Medicine published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C25H29N9O3, HPLC of Formula: 377727-87-2.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Carlin, Jesse Lea published the artcileActivation of adenosine A_2A or A_2B receptors causes hypothermia in mice, SDS of cas: 377727-87-2, the publication is Neuropharmacology (2018), 268-278, database is CAplus and MEDLINE.

A review. Extracellular adenosine is a danger/injury signal that initiates protective physiol., such as hypothermia. Adenosine has been shown to trigger hypothermia via agonism at A₁ and A₃ adenosine receptors (A₁AR, A₃AR). Here, we find that adenosine continues to elicit hypothermia in mice null for A₁AR and A₃AR and investigated the effect of agonism at A_2AAR or A_2BAR. The poorly brain penetrant A_2AAR agonists CGS-21680 and PSB-0777 caused hypothermia, which was not seen in mice lacking A_2AAR. MRS7352, a likely non-brain penetrant A_2AAR antagonist, inhibited PSB-0777 hypothermia. While vasodilation is probably a contributory mechanism, A_2AAR agonism also caused hypometabolism, indicating that vasodilation is not the sole mechanism. The A_2BAR agonist BAY60-6583 elicited hypothermia, which was lost in mice null for A_2BAR. Low intracerebroventricular doses of BAY60-6583 also caused hypothermia, indicating a brain site of action, with neuronal activation in the preoptic area and paraventricular nucleus of the hypothalamus. Thus, agonism at any one of the canonical adenosine receptors, A₁AR, A_2AAR, A_2BAR, or A₃AR, can cause hypothermia. This four-fold redundancy in adenosine-mediated initiation of hypothermia may reflect the centrality of hypothermia as a protective response.

Neuropharmacology published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C25H29N9O3, SDS of cas: 377727-87-2.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Alnouri, Mohamad Wessam published the artcileSelectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors, Formula: C25H29N9O3, the publication is Purinergic Signalling (2015), 11(3), 389-407, database is CAplus and MEDLINE.

Adenosine receptors (ARs) have emerged as new drug targets. The majority of data on affinity/potency and selectivity of AR ligands described in the literature has been obtained for the human species. However, preclin. studies are mostly performed in mouse or rat, and standard AR agonists and antagonists are frequently used for studies in rodents without knowing their selectivity in the investigated species. In the present study, we selected a set of frequently used standard AR ligands, 8 agonists and 16 antagonists, and investigated them in radioligand binding studies at all four AR subtypes, A₁, A_2A, A_2B, and A₃, of three species, human, rat, and mouse. Recommended, selective agonists include CCPA (for A₁AR of rat and mouse), CGS-21680 (for A_2A AR of rat), and Cl-IB-MECA (for A₃AR of all three species). The functionally selective partial A_2B agonist BAY60-6583 was found to addnl. bind to A₁ and A₃AR and act as an antagonist at both receptor subtypes. The antagonists PSB-36 (A₁), preladenant (A_2A), and PSB-603 (A_2B) displayed high selectivity in all three investigated species. MRS-1523 acts as a selective A₃AR antagonist in human and rat, but is only moderately selective in mouse. The comprehensive data presented herein provide a solid basis for selecting suitable AR ligands for biol. studies.

Purinergic Signalling published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C25H29N9O3, Formula: C25H29N9O3.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics