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Beilstein Journal of Organic Chemistry 20242-Chloro-4-sulfonylquinazolines undergo functional group swap when treated with an azide nucleophile: 1) the azide replaces the sulfonyl group at the C4 position; 2) the...
2-Chloro-4-sulfonylquinazolines undergo functional group swap when treated with an azide nucleophile: 1) the azide replaces the sulfonyl group at the C4 position; 2) the intrinsic azide-tetrazole tautomeric equilibrium directs the nucleofugal sulfinate from the first step to replace chloride at the C2 position. This transformation is effective with quinazolines bearing electron-rich substituents. Therefore, the title transformations are demonstrated on the 6,7-dimethoxyquinazoline core, which is present in pharmaceutically active substances. The methodology application is showcased by transforming the obtained 4-azido-6,7-dimethoxy-2-sulfonylquinazolines into the α-adrenoceptor blockers terazosin and prazosin by further C2-selective SAr reaction and azide reduction.
PubMed: 38590535
DOI: 10.3762/bjoc.20.61 -
The Primary Care Companion For CNS... Mar 2024
Topics: Humans; Dreams; Prazosin; Clinical Trials as Topic
PubMed: 38442072
DOI: 10.4088/PCC.23cr03638 -
Proceedings of the National Academy of... Feb 2024The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding...
The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson's disease (PD) in which decreased neuronal energy metabolism is a hallmark feature. TZ was neuroprotective in cell-based and animal PD models and in large epidemiological studies of humans. However, how TZ might increase PGK1 activity has remained a perplexing question because structural data revealed that the site of TZ binding to PGK1 overlaps with the site of substrate binding, predicting that TZ would competitively inhibit activity. Functional data also indicate that TZ is a competitive inhibitor. To explore the paradoxical observation of a competitive inhibitor increasing enzyme activity under some conditions, we developed a mass action model of TZ and PGK1 interactions using published data on PGK1 kinetics and the effect of varying TZ concentrations. The model indicated that TZ-binding introduces a bypass pathway that accelerates product release. At low concentrations, TZ binding circumvents slow product release and increases the rate of enzymatic phosphotransfer. However, at high concentrations, TZ inhibits PGK1 activity. The model explains stimulation of enzyme activity by a competitive inhibitor and the biphasic dose-response relationship for TZ and PGK1 activity. By providing a plausible mechanism for interactions between TZ and PGK1, these findings may aid development of TZ or other agents as potential therapeutics for neurodegenerative diseases. The results may also have implications for agents that interact with the active site of other enzymes.
Topics: Humans; Animals; Phosphoglycerate Kinase; Prazosin; Parkinson Disease; Glycolysis
PubMed: 38377207
DOI: 10.1073/pnas.2318956121 -
Annals of Medicine and Surgery (2012) Feb 2024Lewy body dementia (LBD) is situated at the convergence of neurodegenerative disorders, posing an intricate and diverse clinical dilemma. The accumulation of abnormal... (Review)
Review
Lewy body dementia (LBD) is situated at the convergence of neurodegenerative disorders, posing an intricate and diverse clinical dilemma. The accumulation of abnormal protein in the brain, namely, the Lewy body causes disturbances in typical neural functioning, leading to a range of cognitive, motor, and mental symptoms that have a substantial influence on the overall well-being and quality of life of affected individuals. There is no definitive cure for the disease; however, several nonpharmacological and pharmacological modalities have been tried with questionable efficacies. The aim of this study is to figure out the role of different interventional strategies in the disease. Donepezil, rivastigmine, memantine, and galantamine were the commonly used drugs for LBD. Together with that, levodopa, antipsychotics, armodafinil, piracetam, and traditional medications like yokukansan were also used, when indicated. Talking about nonpharmacological measures, exercise, physical therapy, multicomponent therapy, occupational therapy, psychobehavioral modification, transcranial stimulation, and deep brain stimulation have been used with variable efficacies. Talking about recent advances in the treatment of LBD, various disease-modifying therapies like ambroxol, neflamapimod, irsenontrine, nilotinib, bosutinib, vodobatinib, clenbuterol, terazosin, elayta, fosgonimeton, and anle138b are emerging out. However, there drugs are still in the different phases of clinical trials and are not commonly used in clinical practice. With the different pharmacological and nonpharmacological modalities we have for treatment of LBD, all of them offer symptomatic relief only. Being a degenerative disease, definite cure of the disease can only be possible with regenerative measures.
PubMed: 38333295
DOI: 10.1097/MS9.0000000000001664 -
European Journal of Pharmacology Apr 2024Abdominal aortic aneurysm (AAA), a vascular degenerative disease, is a potentially life-threatening condition characterised by the loss of vascular smooth muscle cells...
Abdominal aortic aneurysm (AAA), a vascular degenerative disease, is a potentially life-threatening condition characterised by the loss of vascular smooth muscle cells (VSMCs), degradation of extracellular matrix (ECM), inflammation, and oxidative stress. Despite the severity of AAA, effective drugs for treatment are scarce. At low doses, terazosin (TZ) exerts antiapoptotic and anti-inflammatory effects in several diseases, but its potential to protect against AAA remains unexplored. Herein, we investigated the effects of TZ in two AAA animal models: Angiotensin II (Ang II) infusion in Apoe mice and calcium chloride application in C57BL/6J mice. Mice were orally administered with TZ (100 or 1000 μg/kg/day). The in vivo results indicated that low-dose TZ alleviated AAA formation in both models. Low-dose TZ significantly reduced aortic pulse wave velocity without exerting an apparent antihypertensive effect in the Ang II-induced AAA model. Paternally expressed gene 3 (Peg3) was identified via RNA sequencing as a novel TZ target. PEG3 expression was significantly elevated in both mouse and human AAA tissues. TZ suppressed PEG3 expression and reduced the abundance of matrix metalloproteinases (MMP2/MMP9) in the tunica media. Functional experiments and molecular analyses revealed that TZ (10 nM) treatment and Peg3 knockdown effectively prevented Ang II-induced VSMC senescence and apoptosis in vitro. Thus, Peg3, a novel target of TZ, mediates inflammation-induced VSMC apoptosis and senescence. Low-dose TZ downregulates Peg3 expression to attenuate AAA formation and ECM degradation, suggesting a promising therapeutic strategy for AAA.
Topics: Mice; Humans; Animals; Muscle, Smooth, Vascular; Pulse Wave Analysis; Mice, Knockout; Mice, Inbred C57BL; Aortic Aneurysm, Abdominal; Apoptosis; Inflammation; Angiotensin II; Disease Models, Animal; Myocytes, Smooth Muscle; Kruppel-Like Transcription Factors; Prazosin
PubMed: 38331337
DOI: 10.1016/j.ejphar.2024.176397 -
Cureus Dec 2023Benign Prostatic Hyperplasia (BPH) is a prevalent condition that affects aging men, leading to the development of lower urinary tract symptoms (LUTS) and potentially... (Review)
Review
Benign Prostatic Hyperplasia (BPH) is a prevalent condition that affects aging men, leading to the development of lower urinary tract symptoms (LUTS) and potentially severe complications such as complete obstruction. The management of BPH typically involves the use of medications from different classes, including alpha-1 antagonists, 5-alpha reductase inhibitors, and anticholinergics. Combination therapy utilizing drugs from different classes can also effectively manage the BPH-LUTS complex. Recent research has revealed that phosphodiesterase 5 (PDE5) inhibitors, including Tadalafil and Sildenafil, are highly effective in treating LUTS associated with BPH. Tadalafil as a monotherapy has recently been shown to significantly improve LUTS in BPH patients. Additionally, the use of herbal remedies as a treatment option for BPH has also been widely debated. Previous research suggests that saw palmetto can reduce BPH symptoms through several proposed mechanisms, but recent trials have found inconsistencies in its efficacy. In this literature review, we conducted an extensive PubMed database search to provide current and comprehensive insights into BPH treatment options. This review comprehensively evaluates available treatments for managing BPH, highlighting the effectiveness of different classes of medications and combination therapies in managing associated symptoms. The present investigation also discusses recent research on the efficacy of PDE5 inhibitors in treating LUTS associated with BPH and the uncertain efficacy of herbal remedies. The insights provided by this study can guide healthcare professionals in making informed decisions about managing BPH, ultimately improving patient outcomes.
PubMed: 38288222
DOI: 10.7759/cureus.51314 -
Archivos Espanoles de Urologia Oct 2023This study aimed to explore the effect of terazosin hydrochloride combined with interventional embolisation on prostate volume and quality of life (QOL) of elderly...
OBJECTIVE
This study aimed to explore the effect of terazosin hydrochloride combined with interventional embolisation on prostate volume and quality of life (QOL) of elderly patients with prostatic hyperplasia (PH).
METHODS
The clinical data of 175 elderly patients with PH admitted to Central Hospital Affiliated to Shandong First Medical University from July 2020 to July 2022 were selected for retrospective analysis. Based on different treatment regimens, 89 patients who received interventional embolisation alone were included in the control group (CG), and 86 patients undergoing interventional embolisation combined with terazosin hydrochloride were included in the study group (SG). The prostate volume, serum indicators, adverse reactions and QOL of the two groups before and after treatment were compared between the two groups.
RESULTS
Before treatment, no significant difference in 36-item short-form health survey (SF-36) scores, serum tumour necrosis factor-α (TNF-α) and prostate-specific antigen (PSA) was observed in both groups ( > 0.05). After treatment, the SF-36 score in the SG was 78.20 ± 6.84 points, which was significantly higher than that in the CG (72.67 ± 5.94 points). In addition, the SG had remarkably lower residual urine volume and prostate volume, higher maximum flow rate and lower TNF-α and PSA levels compared with the CG ( < 0.05). The adverse reaction rate of the SG was only 4.65%, which was significantly lower than that of the CG (14.61%, < 0.05).
CONCLUSIONS
Terazosin hydrochloride combined with interventional embolisation overtly reduces the prostate volume and improves the clinical symptoms of patients with fewer side effects, which has a certain clinical application value.
Topics: Aged; Humans; Male; Adrenergic alpha-Antagonists; Prostate; Prostate-Specific Antigen; Prostatic Hyperplasia; Quality of Life; Retrospective Studies; Treatment Outcome; Tumor Necrosis Factor-alpha; Embolization, Therapeutic; Urological Agents
PubMed: 37960955
DOI: 10.56434/j.arch.esp.urol.20237608.70 -
Medical Science Monitor : International... Sep 2023BACKGROUND This study aimed to compare the impact of a-1 adrenergic blockers - nonselective (alfuzosin, doxazosin, and terazosin) and selective (silodosin and... (Observational Study)
Observational Study
BACKGROUND This study aimed to compare the impact of a-1 adrenergic blockers - nonselective (alfuzosin, doxazosin, and terazosin) and selective (silodosin and tamsulosin) - on the sedative effects of the alpha-2 adrenergic agonist dexmedetomidine (DMT) in patients undergoing urologic surgery. The primary outcome was the sedative effect of DMT as determined by the bispectral index (BIS) and Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale scores. MATERIAL AND METHODS One hundred eighteen patients undergoing elective urologic surgery with spinal anesthesia were recruited. Patients were assigned based on their medication status to group N (no medication; n=33), group NS (nonselective alpha-1 blocker; n=27), or group S (selective alpha-1 blocker; n=58). Mean blood pressure (MBP), heart rate (HR), oxygen saturation (SpO₂), BIS, and MOAA/S scale scores were recorded at 5-minute (min) intervals after DMT administration. RESULTS Group NS had significantly higher BIS scores than groups N and S at 25 min (P=0.045) and 30 min (P=0.030) after DMT administration, indicating lower sedation levels. MBP significantly differed between the 3 groups at all time points, with group N experiencing a lower MBP than groups NS and S. No significant differences were found between the groups in MOAA/S scale scores, SpO₂, or HR. CONCLUSIONS Nonselective alpha-1 adrenergic blockers can reduce the sedative effects of DMT. Consequently, there may be a need for individualized anesthesia management considering the specific subtype of alpha-1 adrenergic blocker medication.
Topics: Humans; Dexmedetomidine; Prospective Studies; Adrenergic alpha-1 Receptor Antagonists; Anesthesia, Spinal; Hypnotics and Sedatives
PubMed: 37747845
DOI: 10.12659/MSM.941614 -
Scientific Reports May 2023Stress is one of the critical facilitators for seizure induction in patients with epilepsy. However, the neural mechanisms underlying this facilitation remain poorly...
Stress is one of the critical facilitators for seizure induction in patients with epilepsy. However, the neural mechanisms underlying this facilitation remain poorly understood. Here, we investigated whether noradrenaline (NA) transmission enhanced by stress exposure facilitates the induction of medial prefrontal cortex (mPFC)-originated seizures. In mPFC slices, whole-cell current-clamp recordings revealed that bath application of picrotoxin induced sporadic epileptiform activities (EAs), which consisted of depolarization with bursts of action potentials in layer 5 pyramidal cells. Addition of NA dramatically shortened the latency and increased the number of EAs. Simultaneous whole-cell and field potential recordings revealed that the EAs are synchronous in the mPFC local circuit. Terazosin, but not atipamezole or timolol, inhibited EA facilitation, indicating the involvement of α adrenoceptors. Intra-mPFC picrotoxin infusion induced seizures in mice in vivo. Addition of NA substantially shortened the seizure latency, while co-infusion of terazosin into the mPFC inhibited the effect of NA. Finally, acute restraint stress shortened the latency of intra-mPFC picrotoxin infusion-induced seizures, whereas prior infusion of terazosin reversed this stress-induced shortening of seizure latency. Our findings suggest that stress facilitates the induction of mPFC-originated seizures via NA stimulation of α adrenoceptors.
Topics: Rats; Mice; Animals; Rats, Sprague-Dawley; Picrotoxin; Norepinephrine; Prefrontal Cortex; Seizures; Receptors, Adrenergic
PubMed: 37208473
DOI: 10.1038/s41598-023-35242-0 -
Journal of Inflammation Research 2023Although Ge-Gen decoction (GGD) has beneficial effects on primary dysmenorrhea (PD), the underlying mechanisms remain poorly understood. Our previous proteomic data...
OBJECTIVE
Although Ge-Gen decoction (GGD) has beneficial effects on primary dysmenorrhea (PD), the underlying mechanisms remain poorly understood. Our previous proteomic data revealed decreased level of heat shock protein 90 (HSP90) in uterine tissues of rats with PD after GGD treatment. However, the potential role of HSP90 in the anti-PD effect of GGD and the underlying mechanisms remain unexplored. This study investigated the potential role and mechanism of HSP90 in the anti-PD effect of GGD using a PD rat model.
METHODS
Wistar female rats were used to investigate the potential role of HSP90 in the anti-PD effect of GGD. The rat PD model was established by injecting estradiol benzoate and oxytocin. GGD, Terazosin (an agonist of HSP90) or GGD combined with Terazosin were orally administered to the PD rats. The expression levels of protein and cytokines, including HSP90, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (COX-2) in the uterine tissue of rats in each group were detected by immunohistochemical assay or Western blot.
RESULTS
GGD ameliorated the writhing response, suppressed the protein levels of HSP90 and inflammation-associated proteins, including NLRP3, NF-κB, and COX-2 in uterine tissues of rats with PD. Terazosin attenuated the anti-PD effect of GGD and reversed the effects of GGD on the protein levels of NLRP3, NF-κB and COX-2 in uterine tissues.
CONCLUSION
GGD exerts an anti-PD effect and suppresses levels of HSP90 and some inflammation associated proteins in uterine tissues of rats.
PubMed: 37092132
DOI: 10.2147/JIR.S400545