Journal of Receptors and Signal Transduction最新文献

{"title":"Exploring the composition of protein-ligand binding sites for cancerous inhibitor of PP2A (CIP2A) by inhibitor guided binding analysis: paving a new way for the Discovery of drug candidates against triple negative breast cancer (TNBC).","authors":"Oluwayimika Ibitoye, Mahmoud A A Ibrahim, Mahmoud E S Soliman","doi":"10.1080/10799893.2023.2298903","DOIUrl":"10.1080/10799893.2023.2298903","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is associated with high-grade invasive carcinoma leading to a 10% to 15% death rate in younger premenopausal women. Targeting cancerous inhibitors of protein phosphatase (CIP2A) has been a highly effective approach for exploring therapeutic drug candidates. Lapatinib, a dual tyrosine kinase inhibitor, has shown promising inhibition properties by inducing apoptosis in TNBC carcinogenesis <i>in vivo</i>. Despite knowledge of the 3D structure of CIP2A, no reports provide insight into CIP2A ligand binding sites. To this effect, we conducted <i>in silico</i> site identification guided by lapatinib binding. Four of the five sites identified were cross-validated, and the stem domain revealed more excellent ligand binding affinity. The binding affinity of lapatinib in these sites was further computed using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) approach. According to MM/PBSA//200 ns MD simulations, lapatinib exhibited a higher binding affinity against CIP2A in site 2 with Δ<i>G</i> critical values of -37.1 kcal/mol. The steadiness and tightness of lapatinib with CIP2A inside the stem domain disclosed glutamic acid-318 as the culprit amino acid with the highest electrostatic energy. These results provide clear information on the CIP2A domain capable of ligand binding and validate lapatinib as a promising CIP2A inhibitor in TNBC carcinogenesis.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"133-143"},"PeriodicalIF":2.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New synthetic derivatives of isoindoline-dione: synthesis, neuroprotection assay and impact on the expression level of oxidative stress-related genes in neuronal-like cell line.","authors":"Abdolrahim Pourparizi, Mina Vazirinia, Fatemeh Pourrajab, Hamid Nadri, Asghar Davood","doi":"10.1080/10799893.2023.2291559","DOIUrl":"10.1080/10799893.2023.2291559","url":null,"abstract":"<p><strong>Purpose: </strong>Oxidative stress can damage cells and cause age-related illnesses such as Alzheimer's, Parkinson's, and Huntington's. This study looked at newly synthesized isoindole derivatives and their effects on SH-SY5Y as a neuroblastoma cell under oxidative stress through the NRF2 signaling pathway. NRF2 transcription factor plays a vital role in the oxidative stress response and cellular homeostasis.</p><p><strong>Method: </strong>Three isoindoline-dione derivatives were synthesized by reacting phthalic anhydrides with 4-(2-aminoethyl)-1-benzyl piperidine. Their structures were confirmed through FT-IR, NMR, and Mass spectroscopy. The derivatives were then tested on human SH-SY5Y cells under an oxidative stress model induced by hydrogen peroxide (H₂O₂). The cell viability, ROS levels, protein carbonyl content, and gene expression of NRF2 and phase II antioxidative enzymes were measured after 24 h.</p><p><strong>Results: </strong>Three isoindoline derivatives <b>(3a-3c)</b> were observed to increase the viability of SH-SY5Y cells by protective against oxidative stress, reducing intracellular reactive oxygen species and carbonylated proteins, and increasing gene expression levels of NRF2 and associated genes such as NQO-1, and GSTK1.</p><p><strong>Conclusion: </strong>Isoindoline derivatives demonstrated a neuroprotective effect on SH-SY5Y cells through various neuroprotective mechanisms, although more studies are needed.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"123-132"},"PeriodicalIF":2.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139545446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA-124a regulates the differentiation of bone marrow mesenchymal stem cells into neurons.","authors":"Eryi Zhao, Daimei Wang, Lijun Jing, Zhongyan Zhao, Shixiong Huang, Ling Xie, Shijun Hu, Hui Liang, Yanquan Chen","doi":"10.1080/10799893.2024.2303014","DOIUrl":"10.1080/10799893.2024.2303014","url":null,"abstract":"<p><strong>Objective: </strong>This study investigated the effects of microRNA-124a on the differentiation of bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanism.</p><p><strong>Methods: </strong>Flow cytometry was used for isolation and identification of BMSCs. Real-time polymerase chain reaction (RT-PCR) was used to detect gene mRNA expression. Apoptosis was detected using Annexin V-FITC/PI Apoptosis Detection Kit. Cell proliferation ability was tested using Cell Counting Kit-8 (CCK-8). The differentiation of BMSCs into neuron inducers β-thiol ethanol or baicalin formed the basis of the study.</p><p><strong>Results: </strong>β-thiol ethanol markedly suppressed the microRNA-124a expression of BMSCs, baicalin markedly induced the microRNA-124a expression of BMSCs and β-thiol ethanol or baicalin promoted apoptosis and reduced the growth of BMSCs. Only the microRNA-124a inhibitor did not affect apoptosis or the differentiation of BMSCs, and it increased the effects of β-thiol ethanol or baicalin on the apoptosis of BMSCs.</p><p><strong>Conclusion: </strong>β-thiol ethanol and baicalin treatment could affect microRNA-124a expression in BMSCs. We demonstrated that microRNA-124a promoted the differentiation of BMSCs into neurons.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"154-159"},"PeriodicalIF":2.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular docking and toxicity studies of nerve agents against acetylcholinesterase (AChE).","authors":"Mikael Ham Sembiring, Okta Nursanti, Tesia Aisyah Rahmania","doi":"10.1080/10799893.2023.2298899","DOIUrl":"10.1080/10799893.2023.2298899","url":null,"abstract":"<p><p>Acetylcholinesterase (AChE) is a cholinergic enzyme that plays an essential role in the autonomic nervous system. This enzyme is often the target of many nerve agents. When this enzyme is inhibited, its function to hydrolyze acetylcholine is stopped, accumulating the acetylcholine in the tissue and causing prolonged stimulation. Some of the significant nerve agents include sarin (GB), soman (GD), tabun (GA), and venomous agent (VX). In order to determine which compound is the most stable and has the best affinity, the nerve agent venomous agent (VX), sarin (GB), soman (GD), and tabun (GA) are docked to the acetylcholinesterase (AChE) enzyme. After that, toxicity tests will be performed on 17 targets for the compound that was chosen. Autodock Vina 1.2.0 is the software used for the docking procedure. should use the Pymol program version 2.5.4 for analysis and the Ligplot software version 2.2 for visualization of the docking findings. The 'Tox Prediction' algorithm from Insilico was used to determine the toxicity of various substances. Based on the results of molecular docking, the free binding energy of Donepezil, sarin (GB), soman (GD), tabun (GA), and venomous agent (VX) in kcal/mol are -12,3, -4.8, -6.0, -5,1, and -6.3 respectively. Finally, four ligands bind strongly to the receptor Donepezil at RMSD 0.327 Å, and the venomous agent (VX) compound binds the most strongly compared to the other test ligands. Furthermore, in the toxicity test of Compound VX, which exhibits neurotoxic activity, no toxic activity was observed on specific organs and targets.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"115-122"},"PeriodicalIF":2.8,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139377902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative structure activity relationship (QSAR) modeling study of some novel thiazolidine 4-one derivatives as potent anti-tubercular agents.","authors":"Anguraj Moulishankar, Sundarrajan Thirugnanasambandam","doi":"10.1080/10799893.2023.2281671","DOIUrl":"10.1080/10799893.2023.2281671","url":null,"abstract":"<p><p>This study aims to develop a QSAR model for Antitubercular activity. The quantitative structure-activity relationship (QSAR) approach predicted the thiazolidine-4-ones derivative's Antitubercular activity. For the QSAR study, 53 molecules with Antitubercular activity on H37Rv were collected from the literature. Compound structures were drawn by ACD/Labs ChemSketch. The energy minimization of the 2D structure was done using the MM2 force field in Chem3D pro. PaDEL Descriptor software was used to construct the molecular descriptors. QSARINS software was used in this work to develop the 2D QSAR model. A series of thiazolidine 4-one with MIC data were taken from the literature to develop the QSAR model. These compounds were split into a training set (43 compounds) and a test set (10 compounds). The PaDEL software calculated 2300 descriptors for this series of thiazolidine 4-one derivatives. The best predictive Model 4, which has <i>R</i>² of 0.9092, <i>R</i>²adj of 0.8950 and LOF parameter of 0.0289 identify a preferred fit. The QSAR study resulted in a stable, predictive, and robust model representing the original dataset. In the QSAR equation, the molecular descriptor of MLFER_S, GATSe2, Shal, and EstateVSA 6 positively correlated with Antitubercular activity. While the SpMAD_Dzs 6 is negatively correlated with Antitubercular activity. The high polarizability, Electronegativities, Surface area contributions and number of Halogen atoms in the thiazolidine 4-one derivatives will increase the Antitubercular activity.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"83-92"},"PeriodicalIF":2.8,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138291257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effects of salvianolic acid B on intestinal ischemia/reperfusion injury in rats by regulating the AhR/IL-22/STAT6 axis.","authors":"Jinyao Xu, Xiangjun Sun, Feng Qin, Xufeng Wang, Qian Chen, Ruicheng Yan","doi":"10.1080/10799893.2023.2204949","DOIUrl":"10.1080/10799893.2023.2204949","url":null,"abstract":"<p><strong>Purpose: </strong>Intestinal ischemia/reperfusion (I/R) injury (IIRI) is associated with high morbidity and mortality. Salvianolic acid B (Sal-B) could exert neuroprotective effects on reperfusion injury after cerebral vascular occlusion, but its effect on IIRI remains unclear. This study set out to investigate the protective effects of Sal-B on IIRI in rats.</p><p><strong>Methods: </strong>The rat IIRI model was established by occluding the superior mesenteric artery and reperfusion, and they were pretreated with Sal-B and aryl hydrocarbon receptor (AhR) antagonist CH-223191 before surgery. Pathological changes in rat ileum, IIRI degree, and intestinal cell apoptosis were evaluated through hematoxylin-eosin staining, Chiu's score scale, and TUNEL staining, together with the determination of caspase-3, AhR protein level in the nucleus, and STAT6 phosphorylation by Western blotting. The levels of inflammatory cytokines (IL-1β/IL-6/TNF-α) and IL-22 were determined by ELISA and RT-qPCR. The contents of superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) in intestinal tissues were determined by spectrophotometry.</p><p><strong>Results: </strong>Sal-B alleviated IIRI in rats, evidenced by slight villi shedding and villi edema, reduced Chiu's score, and diminished the number of TUNEL-positive cells and caspase-3 expression. SAL-B alleviated inflammation and oxidative stress (OS) responses induced by IIRI. Sal-B promoted IL-22 secretion by activating AhR in intestinal tissue after IIRI. Inhibition of AhR activation partially reversed the protective effect of Sal-B on IIRI. Sal-B promoted STAT6 phosphorylation by activating the AhR/IL-22 axis.</p><p><strong>Conclusion: </strong>Sal-B plays a protective role against IIRI in rats by activating the AhR/IL-22/STAT6 axis, which may be achieved by reducing the intestinal inflammatory response and OS responses.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":" ","pages":"73-82"},"PeriodicalIF":2.8,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9752232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction.","authors":"","doi":"10.1080/10799893.2021.2007625","DOIUrl":"https://doi.org/10.1080/10799893.2021.2007625","url":null,"abstract":"7. Sabour H, Javidan AN, Vafa MR, et al. Calorie and macronutrients intake in people with spinal cord injuries: an analysis by sex and injury-related variables. Nutrition 2012;28:143-7. 8. Turner JE, Markovitch D, Betts JA, Thompson D. Nonprescribed physical activity energy expenditure is maintained with structured exercise and implicates a compensatory increase in energy intake. Am J Clin Nutr 2010;92:1009-16. 9. Fontana L, Villareal DT, Weiss EP, et al. Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial. Am J Physiol Endocrinol Metab 2007; 293:E197-202. 10. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003;108:1664-72. 11. Mora S, Cook N, Buring JE, Ridker PM, Lee IM. Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms. Circulation 2007;116:2110-8. 12. Green DJ, O’Driscoll G, Joyner MJ, Cable NT. Exercise and cardiovascular risk reduction: time to update the rationale for exercise? J Appl Physiol 2008;105:766-8. 13. Green DJ, Maiorana A, O’Driscoll G, Taylor RR. Topical review: effects of exercise training on vascular endothelial nitric oxide function in humans. J Physiol 2004;561:1-25. 14. Dinenno FA, Tanaka H, Monahan KD, et al. Regular endurance exercise induces expansive arterial remodelling in the trained limbs of healthy men. J Physiol 2001;534:287-95. 15. Levy WC, Cerqueira MD, Harp GD, et al. Effect of endurance exercise training on heart rate variability at rest in healthy young and older men. Am J Cardiol 1998;82:1236-41. 16. Tsuji H, Venditti Jr FJ, Manders ES, et al. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation 1994;90:878-83. 17. Latimer AE, Ginis KA, Craven BC, Hicks AL. The physical activity recall assessment for people with spinal cord injury: validity. Med Sci Sports Exerc 2006;38:208-16. 18. Dwyer TJ, Alison JA, McKeough ZJ, Elkins MR, Bye PT. Evaluation of the SenseWear activity monitor during exercise in cystic fibrosis and in health. Respir Med 2009;103:1511-7.","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"43 1","pages":"27-30"},"PeriodicalIF":2.8,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9608463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogen receptors as potential therapeutic target in endometrial cancer.","authors":"Payel Guha,&nbsp;Koushik Sen,&nbsp;Piyali Chowdhury,&nbsp;Dilip Mukherjee","doi":"10.1080/10799893.2023.2187643","DOIUrl":"https://doi.org/10.1080/10799893.2023.2187643","url":null,"abstract":"<p><p>Endometrial cancer (EC) is one of the most common gynecological carcinomas in both developed and developing countries. Majority of the gynecological malignancies are hormonally driven where estrogen signaling acts as an oncogenic signal. Estrogen's effects are mediated <i>via</i> classical nuclear estrogen receptors; estrogen receptor alpha and beta (ERα and ERβ) and a trans-membrane G protein-coupled estrogen receptor (GPR30 and GPER). ERs and GPER through ligand binding triggers multiple downstream signaling pathways causing cell cycle regulation, cell differentiation, migration, and apoptosis in various tissues including endometrium. Although the molecular aspect of estrogen function in ER-mediated signaling is now partly understood, the same is not true for GPER-mediated signaling in endometrial malignancies. Understanding the physiological roles of ERα and GPER in EC biology therefore leads to the identification of some novel therapeutic targets. Here we review the effect of estrogen signaling through ERα-and GPER in EC, major types, and some affordable treatment approaches for endometrial tumor patients which has interesting implications in understanding uterine cancer progression.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"43 1","pages":"19-26"},"PeriodicalIF":2.8,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9274049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone marrow mesenchymal stem cells inhibit ferroptosis via regulating the Nrf2-keap1/p53 pathway to ameliorate chronic kidney disease injury in the rats.","authors":"Lishi Shao,&nbsp;Qixiang Fang,&nbsp;Chen Shi,&nbsp;Ya Zhang,&nbsp;Chunjuan Xia,&nbsp;Yifan Zhang,&nbsp;Jiaping Wang,&nbsp;Fukun Chen","doi":"10.1080/10799893.2023.2185083","DOIUrl":"https://doi.org/10.1080/10799893.2023.2185083","url":null,"abstract":"<p><strong>Purpose: </strong>Although bone marrow mesenchymal stem cells (BMMSCs) have been reported to exhibit a protective effect on animal models of chronic kidney disease (CKD), the exact mechanisms involved require further investigation. This study aims to investigate the underlying molecular mechanisms of BMMSCs in inhibiting ferroptosis and preventing an Adriamycin (ADR)-induced CKD injury.</p><p><strong>Methods: </strong>A rat model of long-term CKD induced through the injection of ADR administered twice weekly <i>via</i> the tail vein was used in this study. After BMMSCs were systemically administered through the renal artery, pathological staining, western blotting, ELISA, and transmission electron microscopy were used to analyze ferroptosis.</p><p><strong>Results: </strong>Analyses of renal function and histopathological findings indicated that ADR-mediated renal dysfunction improved in response to the BMMSC treatment, which was also sufficient to mediate the partial reversal of renal injury and mitochondrial pathological changes. BMMSCs decreased the ferrous iron (Fe²⁺) and reactive oxygen species and elevated glutathione (GSH) and GSH peroxidase 4. Moreover, the BMMSC treatment activated the expression of ferroptosis-related regulator NF-E2-related factor 2 (Nrf2) and inhibited Keap1 and p53 in CKD rat kidney tissues.</p><p><strong>Conclusions: </strong>BMMSCs alleviate CKD, possibly resulting from the inhibition of kidney ferroptosis by regulating the Nrf2-Keap1/p53 pathway.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"43 1","pages":"9-18"},"PeriodicalIF":2.8,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9632244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2-{N-[(2,4,5-trichlorophenoxy) acetyl]-N-methylamino}-3-pyrrolidinepropanamide analogs as potential antagonists of Urotensin II receptor.","authors":"Ajay Soni,&nbsp;Subham Saha,&nbsp;Aditi Agarwal,&nbsp;Abdul Rehman Abdul Rauf,&nbsp;Rakesh Kumar Singh,&nbsp;Mahesh Seth,&nbsp;Shashi Kant Singh,&nbsp;Sandeep Sinha,&nbsp;Raj Kumar Shirumalla,&nbsp;Shinji Marumoto,&nbsp;Ruchi Tandon","doi":"10.1080/10799893.2022.2164306","DOIUrl":"https://doi.org/10.1080/10799893.2022.2164306","url":null,"abstract":"<p><strong>The purpose of the article: </strong>To identify novel small molecule antagonists of Urotensin II receptor with acceptable pharmacological profile.</p><p><strong>Materials and methods: </strong>Structure-activity-relationship (SAR) studies on 2-{<i>N</i>-[(2,4,5-trichlorophenoxy) acetyl]-<i>N</i>-methylamino}-3-pyrrolidinepropanamide series were conducted and shortlisted compounds were synthesized and evaluated in <i>in vitro</i> cell-based assays. Human and mouse Urotensin II receptor overexpressing CHO cells were used for calcium release and radioligand binding assays. Initial molecules in this series had solubility and inter-species variability issue in the calcium release assay. We, therefore, conducted SAR to overcome these 2 issues and molecules with accepted <i>in vitro</i> profile were evaluated further in mouse pressor response model to generate the <i>in vivo</i> proof of concept for UII receptor antagonization.</p><p><strong>Results and conclusions: </strong>We report herewith identification of 2-{<i>N</i>-[(2,4,5-trichlorophenoxy)acetyl]-<i>N</i>-methylamino}-3-pyrrolidinepropanamides series to obtain novel small molecule antagonists of Urotensin II receptor with acceptable pharmacological profile.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":"43 1","pages":"1-8"},"PeriodicalIF":2.8,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9263238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}