Chiral drug naftopidil(NAF), a specific α1D-adrenoceptor(AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers s...Chiral drug naftopidil(NAF), a specific α1D-adrenoceptor(AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers showed the same antagonistic effects on the α1D-AR, but the binding mechanism of these two stereochemical NAF isomers to the α1D receptor remained unclear. Herein, we reported the crystallographic structures of optically pure NAF stereoisomers for the first time and unambiguously determined their absolute configurations. The crystal data of R and S enantiomers matched satisfactorily the pharmacophore model for α1D-selective antagonists. Based on the constructed α1D homology model,molecular docking studies shed light on the molecular mechanism of NAF enantiomers binding to α1D-AR. The results indicated that NAF enantiomers exhibited the very similar binding poses and occupied the same binding pocket.展开更多
A series of arylpiperazinesquinazoline-2,4-diamine compounds were designed and synthesized based on pharmacophore for m-selective α1-adrenoceptor antagonists and 3D chemical database searching. The in vitro functiona...A series of arylpiperazinesquinazoline-2,4-diamine compounds were designed and synthesized based on pharmacophore for m-selective α1-adrenoceptor antagonists and 3D chemical database searching. The in vitro functional analysis showed that compounds 9 and 14 showed better and similar α1-AR antagonistic activity compared with prazosin.展开更多
Two series of 1-（benzoxazole-2-yl）piperazine （Sa-i） and 4-（benzoxazole-2-yl）piperidine compounds （10a-i） were designed, synthesized and evaluated for their α1-AR antagonistic activities. Biological assay in v...Two series of 1-（benzoxazole-2-yl）piperazine （Sa-i） and 4-（benzoxazole-2-yl）piperidine compounds （10a-i） were designed, synthesized and evaluated for their α1-AR antagonistic activities. Biological assay in vitro indicated that 10h showed slightly stronger α1-AR antagonistic activity to that of our lead compound 1.展开更多
Aim and methods The study of three-dimensional quantitative structure-activity relationship （3D-QSAR） of DDPH and its derivatives has been performed using Apex-3D programme. Results The result indicates that substit...Aim and methods The study of three-dimensional quantitative structure-activity relationship （3D-QSAR） of DDPH and its derivatives has been performed using Apex-3D programme. Results The result indicates that substituents of para- and ortho-positions in phenyl ring of aryloxyalkylamine greatly influence the bioactivity. Conclusion The biophore model and 3D-QSAR equation help us not only further understand receptor-ligand interactions, but also design new compounds with better bioactivity.展开更多
AIM: To assess the effect of non-selective ETA/B (LU 302872)and selective ETA (LU 302146) antagonist on pancreatic histology and ultrastructure of acinar cells in connection with trypsinogen activation in early caerul...AIM: To assess the effect of non-selective ETA/B (LU 302872)and selective ETA (LU 302146) antagonist on pancreatic histology and ultrastructure of acinar cells in connection with trypsinogen activation in early caerulein-induced AP.METHODS: Male Wistar rats with caerulein-induced AP,lasting 4 h, were treated i.p. with 10 and 20 mg/kg b.w.of each antagonist. Edema, inflammatory infiltration,necrosis and vacuolization of acinar cells in the pancreas were scored at 0-3 scale. Free active trypsin (FAT), total potential trypsin (TPT) after activation with enterokinase,and index of trypsinogen activation (%FAT/TPT) were assayed in pancreatic homogenates.RESULTS: In untreated AP, the edema, inflammatory infiltration, necrosis and vacuolization increased as compared to control healthy rats (P＜0.01). None of the treatment exerted any meaningful effect on the edema and inflammatory infiltration. The selective antagonist increased slightly the necrosis score to 0.82±0.06 at higher dose (P＜0.05) vs 0.58±0.06 in untreated AP. The nonselective antagonist increased slightly the vacuolization score to 2.41±0.07 at higher dose (P＜0.01) vs 1.88±0.08in untreated AP. The decrease in the number of zymogen granules, disorganization of endoplasmic reticulum,autophagosomes and cytoplasmic vacuoles were more prominent in treated AP than in untreated AP groups.%FAT/TPT in untreated AP increased about four times (18.4±3.8 vs4.8±1.3 in control group without AP, P＜0.001).Treatment of AP with both antagonists did not affect significantly augmented trypsinogen activation.CONCLUSION: The treatment with endothelin-1 receptors (non-selective ETA/B and selective ETA) antagonists has essential effect neither on the edema and inflammatory infiltration nor on trypsinogen activation observed in the early course of caerulein-induced AP. Nevertheless a slight increase of the necrosis and vacuolization score and some of the ultrastructural data could suggest the possibility of their undesired effects in caerulein-induced AP at investigated doses.展开更多
Medical therapy for clinical benign prostatic hyperplasia(BPH)has advanced significantly in the last 2 decades.Many new a1 antagonists and 5a reductase inhibitors(5ARi)are now commercially available.The practicing uro...Medical therapy for clinical benign prostatic hyperplasia(BPH)has advanced significantly in the last 2 decades.Many new a1 antagonists and 5a reductase inhibitors(5ARi)are now commercially available.The practicing urologist must decide on the most appropriate medication for his patients,taking into consideration various factors like efficacy,dosing regime,adverse effects,cost,patient’s socioeconomic background,expectations,drug availability and his own clinical experience.The use of combination therapy added further to the complexity in clinical judgment when prescribing.We highlight some of the key points in prescribing a1 antagonists,5ARi and their combination,based on our viewpoints and experience as urologists in an Asian clinical setting.展开更多
A series of 2-alkylbenzimidazole derivatives 9a-n have been designed and synthesized as a novel class of non-peptide angiotensin H AT1 receptor antagonists. The synthesized compounds were evaluated for their antagonis...A series of 2-alkylbenzimidazole derivatives 9a-n have been designed and synthesized as a novel class of non-peptide angiotensin H AT1 receptor antagonists. The synthesized compounds were evaluated for their antagonism of angiotensin H, induced contraction in the rabbit thoracic aortic ring and the results showed that compounds 9a, 9g and 9j exhibited potent antagonistic activity of AT1 receptor.展开更多
A series of 1-[2-(substituted phenoxy)ethyl]-4-(2-methoxyphenyl)-piperazine deriva- tives have been synthesized. The radioligand receptor binding assay indicated that most of them bind with α1-adrenoceptor specific...A series of 1-[2-(substituted phenoxy)ethyl]-4-(2-methoxyphenyl)-piperazine deriva- tives have been synthesized. The radioligand receptor binding assay indicated that most of them bind with α1-adrenoceptor specifically, and one of the compound possessed subtype A selectivity.展开更多
Chemotherapy-induced nausea and vomiting (CINV) are distressing side effects of chemotherapy. Neurokinin-1 receptor antagonists (NK1-RAs) have been incorporated in the contemporary management of CINV. However, clinica...Chemotherapy-induced nausea and vomiting (CINV) are distressing side effects of chemotherapy. Neurokinin-1 receptor antagonists (NK1-RAs) have been incorporated in the contemporary management of CINV. However, clinical studies on NK1-RAs have shown mixed results in reducing CINV risk. Most studies focused on the use of aprepitant (APR) and casopitant (CAS) in breast cancer patients receiving AC-type (doxorubicin and cyclophosphamide) chemotherapy. In this study, we compared the study design and clinical efficacies of these NK1-RAs in reducing CINV risk. Among the selected eight studies, 4 APR Randomized Controlled Trials (RCTs), 2 APR Observational Studies (OSs) and 2 CAS RCTs were identified. Patient-related characteristics such as the proportion of females (60.0% - 100.0%), age (46.5 - 59.5 years), histories of motion (5.6% - 47.0% in NK1-RA arms) and morning sicknesses (14.2% - 45.0% in NK1-RA arms) and types of antiemetic regimens;as well as chemotherapy-related characteristics such as the proportion of patients on AC chemotherapy (15.0% - 100.0%) varied greatly. In terms of efficacies, both APR and CAS improved overall CR and vomiting in majority of the studies. None of the studies, however, demonstrated that NK1-RA could provide adequate nausea control. To conclude, NK1-RAs are effective in improving vomiting and overall CR, but not useful in controlling nausea or attaining CC, the ideal CINV endpoint. A shift in paradigm is needed for future CINV research. As healthcare providers continue to strive for optimum CINV control in their patients, we hope this review can help them make better informed clinical decisions.展开更多
A novel and efficient method was developed for the synthesis of diarylpyrazole derivatives as cannabinoid CB1 receptor antagonist via four step reactions. The key step was the synthesis of a diarylpyrazole skeleton, w...A novel and efficient method was developed for the synthesis of diarylpyrazole derivatives as cannabinoid CB1 receptor antagonist via four step reactions. The key step was the synthesis of a diarylpyrazole skeleton, which involved initial condensation of the sodium salt of compound 12 with diazonium compounds, and further cyclization by heating at reflux in acetic acid. Eight diarylpyrazole derivatives and nine new synthesized compounds were characterized by 1H NMR, IR, MS, and elemental analysis. The reaction conditions were mild and the overall yields of the target compounds ranged from 26% to 44%.展开更多
Background: Studies have shown a strong correlation between the growth of E2 in serum and estrone-3-glucuronide (E1-3G) in urine during ovarian stimulation. Thus, we developed theoretical models for using urinary E1-3...Background: Studies have shown a strong correlation between the growth of E2 in serum and estrone-3-glucuronide (E1-3G) in urine during ovarian stimulation. Thus, we developed theoretical models for using urinary E1-3G in ovarian stimulation and focused on their experimental verification and analysis. Methods: A prospective, observational pilot study was conducted involving 54 patients who underwent 54 cycles of ovarian stimulation. The goal was to establish the growth rate of urinary E1-3G during the course of stimulation and to determine the daily upper and lower limits of growth rates at which stimulation is appropriate and safe. Controlled ovarian stimulation was performed using two different stimulation protocols—an antagonist protocol in 25 cases and a progestin-primed ovarian stimulation protocol (PPOS) in 29 cases, with fixed doses of gonadotropins. From the second day of stimulation, patients self-measured their daily urine E1-3G levels at home using a portable analyzer. In parallel, a standard ultrasound follow-up protocol accompanied by a determination of E2, LH, and P levels was applied to optimally control stimulation. Results: The average daily growth rates in both groups were about 50%. The daily increase in E1-3G for the antagonist protocol ranged from 14% to 79%, while they were 28% to 79% for the PPOS protocol. Conclusion: This is the first study to analyze the dynamics of E1-3G in two different protocols and to estimate the limits of its increase during the entire course of the stimulation. The results confirm our theoretical model for the viability of using urinary E1-3G for monitoring ovarian stimulation.展开更多
Recently, NK1R （Neurokinin-1 receptors） take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibi...Recently, NK1R （Neurokinin-1 receptors） take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.展开更多
基金supported by grants from the National Science Foundation of Guangdong Province (No. S2013040014088)the Postdoctoral Science Foundation of Guangzhou City (Q188)partially supported by the Guangdong Major Scientific and Technological Special Project for New Drug Development (2013A022100029)
文摘Chiral drug naftopidil(NAF), a specific α1D-adrenoceptor(AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers showed the same antagonistic effects on the α1D-AR, but the binding mechanism of these two stereochemical NAF isomers to the α1D receptor remained unclear. Herein, we reported the crystallographic structures of optically pure NAF stereoisomers for the first time and unambiguously determined their absolute configurations. The crystal data of R and S enantiomers matched satisfactorily the pharmacophore model for α1D-selective antagonists. Based on the constructed α1D homology model,molecular docking studies shed light on the molecular mechanism of NAF enantiomers binding to α1D-AR. The results indicated that NAF enantiomers exhibited the very similar binding poses and occupied the same binding pocket.
文摘A series of arylpiperazinesquinazoline-2,4-diamine compounds were designed and synthesized based on pharmacophore for m-selective α1-adrenoceptor antagonists and 3D chemical database searching. The in vitro functional analysis showed that compounds 9 and 14 showed better and similar α1-AR antagonistic activity compared with prazosin.
基金the National High-Tech Research and Development Plan(No.2002AA2Z3118)
文摘Two series of 1-（benzoxazole-2-yl）piperazine （Sa-i） and 4-（benzoxazole-2-yl）piperidine compounds （10a-i） were designed, synthesized and evaluated for their α1-AR antagonistic activities. Biological assay in vitro indicated that 10h showed slightly stronger α1-AR antagonistic activity to that of our lead compound 1.
文摘Aim and methods The study of three-dimensional quantitative structure-activity relationship （3D-QSAR） of DDPH and its derivatives has been performed using Apex-3D programme. Results The result indicates that substituents of para- and ortho-positions in phenyl ring of aryloxyalkylamine greatly influence the bioactivity. Conclusion The biophore model and 3D-QSAR equation help us not only further understand receptor-ligand interactions, but also design new compounds with better bioactivity.
基金Supported by the Medical University of Bialystok within the Project #30-12770
文摘AIM: To assess the effect of non-selective ETA/B (LU 302872)and selective ETA (LU 302146) antagonist on pancreatic histology and ultrastructure of acinar cells in connection with trypsinogen activation in early caerulein-induced AP.METHODS: Male Wistar rats with caerulein-induced AP,lasting 4 h, were treated i.p. with 10 and 20 mg/kg b.w.of each antagonist. Edema, inflammatory infiltration,necrosis and vacuolization of acinar cells in the pancreas were scored at 0-3 scale. Free active trypsin (FAT), total potential trypsin (TPT) after activation with enterokinase,and index of trypsinogen activation (%FAT/TPT) were assayed in pancreatic homogenates.RESULTS: In untreated AP, the edema, inflammatory infiltration, necrosis and vacuolization increased as compared to control healthy rats (P＜0.01). None of the treatment exerted any meaningful effect on the edema and inflammatory infiltration. The selective antagonist increased slightly the necrosis score to 0.82±0.06 at higher dose (P＜0.05) vs 0.58±0.06 in untreated AP. The nonselective antagonist increased slightly the vacuolization score to 2.41±0.07 at higher dose (P＜0.01) vs 1.88±0.08in untreated AP. The decrease in the number of zymogen granules, disorganization of endoplasmic reticulum,autophagosomes and cytoplasmic vacuoles were more prominent in treated AP than in untreated AP groups.%FAT/TPT in untreated AP increased about four times (18.4±3.8 vs4.8±1.3 in control group without AP, P＜0.001).Treatment of AP with both antagonists did not affect significantly augmented trypsinogen activation.CONCLUSION: The treatment with endothelin-1 receptors (non-selective ETA/B and selective ETA) antagonists has essential effect neither on the edema and inflammatory infiltration nor on trypsinogen activation observed in the early course of caerulein-induced AP. Nevertheless a slight increase of the necrosis and vacuolization score and some of the ultrastructural data could suggest the possibility of their undesired effects in caerulein-induced AP at investigated doses.
文摘Medical therapy for clinical benign prostatic hyperplasia(BPH)has advanced significantly in the last 2 decades.Many new a1 antagonists and 5a reductase inhibitors(5ARi)are now commercially available.The practicing urologist must decide on the most appropriate medication for his patients,taking into consideration various factors like efficacy,dosing regime,adverse effects,cost,patient’s socioeconomic background,expectations,drug availability and his own clinical experience.The use of combination therapy added further to the complexity in clinical judgment when prescribing.We highlight some of the key points in prescribing a1 antagonists,5ARi and their combination,based on our viewpoints and experience as urologists in an Asian clinical setting.
基金We are thankful to the National Natural Science Foundation of China(No.30371688)Key Fund of Ministry of Education of China(No.03089)for financial support.
文摘A series of 2-alkylbenzimidazole derivatives 9a-n have been designed and synthesized as a novel class of non-peptide angiotensin H AT1 receptor antagonists. The synthesized compounds were evaluated for their antagonism of angiotensin H, induced contraction in the rabbit thoracic aortic ring and the results showed that compounds 9a, 9g and 9j exhibited potent antagonistic activity of AT1 receptor.
文摘A series of 1-[2-(substituted phenoxy)ethyl]-4-(2-methoxyphenyl)-piperazine deriva- tives have been synthesized. The radioligand receptor binding assay indicated that most of them bind with α1-adrenoceptor specifically, and one of the compound possessed subtype A selectivity.
文摘Chemotherapy-induced nausea and vomiting (CINV) are distressing side effects of chemotherapy. Neurokinin-1 receptor antagonists (NK1-RAs) have been incorporated in the contemporary management of CINV. However, clinical studies on NK1-RAs have shown mixed results in reducing CINV risk. Most studies focused on the use of aprepitant (APR) and casopitant (CAS) in breast cancer patients receiving AC-type (doxorubicin and cyclophosphamide) chemotherapy. In this study, we compared the study design and clinical efficacies of these NK1-RAs in reducing CINV risk. Among the selected eight studies, 4 APR Randomized Controlled Trials (RCTs), 2 APR Observational Studies (OSs) and 2 CAS RCTs were identified. Patient-related characteristics such as the proportion of females (60.0% - 100.0%), age (46.5 - 59.5 years), histories of motion (5.6% - 47.0% in NK1-RA arms) and morning sicknesses (14.2% - 45.0% in NK1-RA arms) and types of antiemetic regimens;as well as chemotherapy-related characteristics such as the proportion of patients on AC chemotherapy (15.0% - 100.0%) varied greatly. In terms of efficacies, both APR and CAS improved overall CR and vomiting in majority of the studies. None of the studies, however, demonstrated that NK1-RA could provide adequate nausea control. To conclude, NK1-RAs are effective in improving vomiting and overall CR, but not useful in controlling nausea or attaining CC, the ideal CINV endpoint. A shift in paradigm is needed for future CINV research. As healthcare providers continue to strive for optimum CINV control in their patients, we hope this review can help them make better informed clinical decisions.
基金Supported by the Program for New Century Excellent Talents in University of China(NosNCET-08-0668, 1154-NCET-002)the Outstanding Youth Foundation of Heilongjiang Province, China(NoJC200706)
文摘A novel and efficient method was developed for the synthesis of diarylpyrazole derivatives as cannabinoid CB1 receptor antagonist via four step reactions. The key step was the synthesis of a diarylpyrazole skeleton, which involved initial condensation of the sodium salt of compound 12 with diazonium compounds, and further cyclization by heating at reflux in acetic acid. Eight diarylpyrazole derivatives and nine new synthesized compounds were characterized by 1H NMR, IR, MS, and elemental analysis. The reaction conditions were mild and the overall yields of the target compounds ranged from 26% to 44%.
文摘Background: Studies have shown a strong correlation between the growth of E2 in serum and estrone-3-glucuronide (E1-3G) in urine during ovarian stimulation. Thus, we developed theoretical models for using urinary E1-3G in ovarian stimulation and focused on their experimental verification and analysis. Methods: A prospective, observational pilot study was conducted involving 54 patients who underwent 54 cycles of ovarian stimulation. The goal was to establish the growth rate of urinary E1-3G during the course of stimulation and to determine the daily upper and lower limits of growth rates at which stimulation is appropriate and safe. Controlled ovarian stimulation was performed using two different stimulation protocols—an antagonist protocol in 25 cases and a progestin-primed ovarian stimulation protocol (PPOS) in 29 cases, with fixed doses of gonadotropins. From the second day of stimulation, patients self-measured their daily urine E1-3G levels at home using a portable analyzer. In parallel, a standard ultrasound follow-up protocol accompanied by a determination of E2, LH, and P levels was applied to optimally control stimulation. Results: The average daily growth rates in both groups were about 50%. The daily increase in E1-3G for the antagonist protocol ranged from 14% to 79%, while they were 28% to 79% for the PPOS protocol. Conclusion: This is the first study to analyze the dynamics of E1-3G in two different protocols and to estimate the limits of its increase during the entire course of the stimulation. The results confirm our theoretical model for the viability of using urinary E1-3G for monitoring ovarian stimulation.
文摘Recently, NK1R （Neurokinin-1 receptors） take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.
