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
Objectives To investigate the changes of β3-adrenoceptor (β3-AR) mRNA expression in the rats with chronic heart failure (CHF), and to explore the effect of β blockers (βBs) on β3 mRNA expression. Methods Thirty-f...Objectives To investigate the changes of β3-adrenoceptor (β3-AR) mRNA expression in the rats with chronic heart failure (CHF), and to explore the effect of β blockers (βBs) on β3 mRNA expression. Methods Thirty-four rats were randomly divided into Sham group (n = 10) and heart failure group (n = 24). Rat model was established by aortic constriction. The survival rats in heart failure group were divided into heart failure control group (HF group, n = 6), metoprolol group (MET group, n = 8) and carvedilol group (CAR group, n = 8) three months after operation. Metoprolol tartarte was started orally with 12 mg·kg-1·d-1, carvedilol with 6 mg·kg-1·d-1, isometric saline was started in HF group. After three months of drug therapy, measurement of hemodynamics, index of ventricular mass, the level of β3-AR mRNA expression were performed. Results Compared with Sham group, left ventricular end systolic pressure (LVESP), and the absolute values of maximal rate of rise and fall ( ± dp/dtmax) of left ventricular pressure were all significantly decreased (P < 0.01), left ventricular end diastolic pressure (LVEDP) was significantly increased in HF group (P < 0.01). The hemodynamic parameters were improved by βBs, and carvedilol was more effective than metoprolol (P < 0.01). The index of ventricular mass was higher in HF group than MET group, CAR group and Sham group (P < 0.01). βBs significantly decreased the index of left ventricular mass (LVMI), and Carvedilol was more effective than metoprolol (P < 0.01). The index of right ventricular mass (RVMI) did not change in MET group (P > 0.05), but significant decrease could be seen in CAR group (P < 0.01). The level of β3-AR expression in left ventricle was greater than that in right ventricle whether in the failing heart or in the non-failing heart. Compared with Sham group, the level of β3-AR mRNA expression was significantly increased in HF group (P < 0.01). The levels of β3-AR mRNA expression showed a remarkable decrease in CAR group(P < 0.01), but was not seen in MET group. Conclusions The β3-AR expression level remarkably increases in the rat’s left and right failing ventricles. Carvedilol is more effective on improving hemodynamics and attenuating ventricular remodeling than metoprolol in the rats with CHF. Carvedilol rather than metoprolol downregulates β3-AR expression in the rat’s failing ventricles. The beneficial effect of carvedilol in CHF maybe partly due to the downregulation of β3-AR expression in the failing heart.展开更多
Objectives To observe the effect of β3-Adrenoceptor （AR） on ventricle fibrillation threshold （VFT） and effective refractory period （ERP） in rats with heart failure. Methods Rats were randomized into control gro...Objectives To observe the effect of β3-Adrenoceptor （AR） on ventricle fibrillation threshold （VFT） and effective refractory period （ERP） in rats with heart failure. Methods Rats were randomized into control group and heart failure group. The expression of β3-ARmRNA was detected with RTPCR; The VFT, ERP, LVESP,LVEDP, ＋dp/dtmax and -dp/dtmax was measured at the same time with administration of BRL37344 （ 2 nmol / kg, β3- AR agonist）. Results ①Both the expression of β3-AR mRNA and the proportion increased in rats with heart failure in comparison with control rats （0.028 vs. 0.011 and 5.4% vs 1.2%, P 〈 0.05）;② ERP was longer in rats with heart failure than control group （70.5±5.5 ms vs 59.5±6.4ms, P 〈 0.05） and there was no difference of ERP in rats with heart failure with administration of BRL37344 （73.0±4.8 ms vs 70.5± 5.5 ms, P 〉0.05）; ③VFT was lower in rats with heart failure than control group（10.9±0.8 mv vs 30.5± 1.3 mv, P〈 0.05） and decreased obviously in rats with heart failure with administration of BRL37344 （7.1±0.6 mv vs 10.9±0.8 mv, P 〈 0.05） ; The decrease of VFT correlated with the effect on LVESP, ＋dp/ dtmax,-dp/dtmax of BRL37344 and the expression of β3-AR mRNA （correlation coefficient： 0.788, 0.708, 0.759, 0.787; P 〈 0.05）. Conclusions The expression of β3-AR mRNA of left ventricle was obviously increased in rats with heart failure, and activation of β3-AR had no effect on ERP but could decreased VFT which correlated with the effect of β3-AR on LVESP, ＋dp/dtmax, -dp/dtmax and the expression of β3-AR mRNA.展开更多
Aim The biophore of uroselective α_1-adrenoceptor antagonist was studied byusing Apex-3D software on an 02 Silicon Graphics Computer Station. Methods Five known antagonists(Indoramin, GG-818, RS100975, R-YM12167, and...Aim The biophore of uroselective α_1-adrenoceptor antagonist was studied byusing Apex-3D software on an 02 Silicon Graphics Computer Station. Methods Five known antagonists(Indoramin, GG-818, RS100975, R-YM12167, and KMD-3213), which possess both good selectivity and highaffinities to prostate and α_1-AR subtype, were chosen for building the biophore. Using anautomatic filtering software for obtaining reasonable biophores, the filter parameters wereselected: P (probability) > 0.8, active (number of active compounds) ≥ 4, and size (descriptorcenter) ≥ 3. Results Three biophores conformed to the requirements, each of whom contained a basiccenter, an aromatic ring center and H-site according to the structure-activity relationships ofknown α_1-adrenoceptor antagonist. Conclusion The biophore model developed by computer simulationwith Apex-3D software can be used to design and synthesize a new α_1-adrenoceptor antagonist withhigh activity and low side effect.展开更多
The nociceptin receptor（NOP） has been involved in multiple biological functions, including pain, anxiety, cough, substance abuse, cardiovascular control, and immunity. Thus, selective NOP agonists might have clinica...The nociceptin receptor（NOP） has been involved in multiple biological functions, including pain, anxiety, cough, substance abuse, cardiovascular control, and immunity. Thus, selective NOP agonists might have clinical potential for the treatment of related diseases. In the present work, three-dimensional quantitative structure-activity relationship（3D-QSAR） studies were performed on a series of 3-substituted N-benzhydryl-nortropane analogs as NOP agonists using comparative molecular field analysis（Co MFA） and comparative molecular similarity indices analysis（CoM SIA） techniques. The statistically significant models were obtained with 54 compounds in training set by ligand-based atom-by-atom matching alignment. The CoM FA model gave cross-validated coefficient（q2） value of 0.530 using 6 components, non-cross-validated（r2） value of 0.921 with estimated F value of 93.668, and standard error of estimate（SEE） of 0.185. The best Co MSIA model resulted in q2 = 0.592, r2 = 0.945, N = 10, SEE = 0.162, and F = 75.654, based on steric, electrostatic, hydrophobic and hydrogen bond acceptor fields. The predictive ability of the Co MFA and CoM SIA models was further validated using a test set of 18 molecules that were not included in the training set, which resulted in predictive correlation coefficients（r2pred） of 0.551 and 0.637, respectively. Moreover, the CoM FA and CoM SIA contour maps identified the features important for exhibiting potent binding affinities on NOP, and can thus serve as a useful guide for the design of potential NOP agonists.展开更多
Objectives To observe the expression of β3-adrenoceptor （β3-AR） of left ventricle and the effect on heart function by stimulating β3-AR in rats with experimental heart failure. Methods Rats were randomly divided ...Objectives To observe the expression of β3-adrenoceptor （β3-AR） of left ventricle and the effect on heart function by stimulating β3-AR in rats with experimental heart failure. Methods Rats were randomly divided into heart failure group and control group. Heart failure models were built up by ligating coronary artery in rats. The expression of β3-AR mRNA were detected with RT-PCR; The change of heart function were observed after administration of BRL37344 （β3-AR agonist） by measuring left ventricular end-systolic pressure （LVESP）, left ventricular end-diastolic pressure （LVEDP）, the maximum pressure ascending rate of left ventricle （＋dp/ dtmax） and the maximum pressure descending rate of left ventricle（-dp/dtmax）. Results The expression of β3-AR mRNA （β3/β-actin） was 0.028±0.005 and the proportion of β3-AR （β3/β1＋β2＋β3） was 5.4%±0.06% in failure rats while the expression of β3-AR mRNA was 0.011 ±0.004 and the proportion was 1.2%±0.04% in control rats; The descending percentage of LVESP, ＋ dp/dtmax and -dp/dtmax were 16.1%, 21.7% and 13.2% respectively with administration of BRL37344 in failure rats, while 12.2%, 15.8% and 11.5% in control rats. Conclusions Compared with control group the expression of β3-AR mRNA of left ventricle was obviously increased and the negative inotropic function with exciting β3-AR was obviously enhanced in failure groups.展开更多
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.
文摘Objectives To investigate the changes of β3-adrenoceptor (β3-AR) mRNA expression in the rats with chronic heart failure (CHF), and to explore the effect of β blockers (βBs) on β3 mRNA expression. Methods Thirty-four rats were randomly divided into Sham group (n = 10) and heart failure group (n = 24). Rat model was established by aortic constriction. The survival rats in heart failure group were divided into heart failure control group (HF group, n = 6), metoprolol group (MET group, n = 8) and carvedilol group (CAR group, n = 8) three months after operation. Metoprolol tartarte was started orally with 12 mg·kg-1·d-1, carvedilol with 6 mg·kg-1·d-1, isometric saline was started in HF group. After three months of drug therapy, measurement of hemodynamics, index of ventricular mass, the level of β3-AR mRNA expression were performed. Results Compared with Sham group, left ventricular end systolic pressure (LVESP), and the absolute values of maximal rate of rise and fall ( ± dp/dtmax) of left ventricular pressure were all significantly decreased (P < 0.01), left ventricular end diastolic pressure (LVEDP) was significantly increased in HF group (P < 0.01). The hemodynamic parameters were improved by βBs, and carvedilol was more effective than metoprolol (P < 0.01). The index of ventricular mass was higher in HF group than MET group, CAR group and Sham group (P < 0.01). βBs significantly decreased the index of left ventricular mass (LVMI), and Carvedilol was more effective than metoprolol (P < 0.01). The index of right ventricular mass (RVMI) did not change in MET group (P > 0.05), but significant decrease could be seen in CAR group (P < 0.01). The level of β3-AR expression in left ventricle was greater than that in right ventricle whether in the failing heart or in the non-failing heart. Compared with Sham group, the level of β3-AR mRNA expression was significantly increased in HF group (P < 0.01). The levels of β3-AR mRNA expression showed a remarkable decrease in CAR group(P < 0.01), but was not seen in MET group. Conclusions The β3-AR expression level remarkably increases in the rat’s left and right failing ventricles. Carvedilol is more effective on improving hemodynamics and attenuating ventricular remodeling than metoprolol in the rats with CHF. Carvedilol rather than metoprolol downregulates β3-AR expression in the rat’s failing ventricles. The beneficial effect of carvedilol in CHF maybe partly due to the downregulation of β3-AR expression in the failing heart.
文摘Objectives To observe the effect of β3-Adrenoceptor （AR） on ventricle fibrillation threshold （VFT） and effective refractory period （ERP） in rats with heart failure. Methods Rats were randomized into control group and heart failure group. The expression of β3-ARmRNA was detected with RTPCR; The VFT, ERP, LVESP,LVEDP, ＋dp/dtmax and -dp/dtmax was measured at the same time with administration of BRL37344 （ 2 nmol / kg, β3- AR agonist）. Results ①Both the expression of β3-AR mRNA and the proportion increased in rats with heart failure in comparison with control rats （0.028 vs. 0.011 and 5.4% vs 1.2%, P 〈 0.05）;② ERP was longer in rats with heart failure than control group （70.5±5.5 ms vs 59.5±6.4ms, P 〈 0.05） and there was no difference of ERP in rats with heart failure with administration of BRL37344 （73.0±4.8 ms vs 70.5± 5.5 ms, P 〉0.05）; ③VFT was lower in rats with heart failure than control group（10.9±0.8 mv vs 30.5± 1.3 mv, P〈 0.05） and decreased obviously in rats with heart failure with administration of BRL37344 （7.1±0.6 mv vs 10.9±0.8 mv, P 〈 0.05） ; The decrease of VFT correlated with the effect on LVESP, ＋dp/ dtmax,-dp/dtmax of BRL37344 and the expression of β3-AR mRNA （correlation coefficient： 0.788, 0.708, 0.759, 0.787; P 〈 0.05）. Conclusions The expression of β3-AR mRNA of left ventricle was obviously increased in rats with heart failure, and activation of β3-AR had no effect on ERP but could decreased VFT which correlated with the effect of β3-AR on LVESP, ＋dp/dtmax, -dp/dtmax and the expression of β3-AR mRNA.
文摘Aim The biophore of uroselective α_1-adrenoceptor antagonist was studied byusing Apex-3D software on an 02 Silicon Graphics Computer Station. Methods Five known antagonists(Indoramin, GG-818, RS100975, R-YM12167, and KMD-3213), which possess both good selectivity and highaffinities to prostate and α_1-AR subtype, were chosen for building the biophore. Using anautomatic filtering software for obtaining reasonable biophores, the filter parameters wereselected: P (probability) > 0.8, active (number of active compounds) ≥ 4, and size (descriptorcenter) ≥ 3. Results Three biophores conformed to the requirements, each of whom contained a basiccenter, an aromatic ring center and H-site according to the structure-activity relationships ofknown α_1-adrenoceptor antagonist. Conclusion The biophore model developed by computer simulationwith Apex-3D software can be used to design and synthesize a new α_1-adrenoceptor antagonist withhigh activity and low side effect.
基金supported by the National Natural Science Foundation of China(No.81101687)
文摘The nociceptin receptor（NOP） has been involved in multiple biological functions, including pain, anxiety, cough, substance abuse, cardiovascular control, and immunity. Thus, selective NOP agonists might have clinical potential for the treatment of related diseases. In the present work, three-dimensional quantitative structure-activity relationship（3D-QSAR） studies were performed on a series of 3-substituted N-benzhydryl-nortropane analogs as NOP agonists using comparative molecular field analysis（Co MFA） and comparative molecular similarity indices analysis（CoM SIA） techniques. The statistically significant models were obtained with 54 compounds in training set by ligand-based atom-by-atom matching alignment. The CoM FA model gave cross-validated coefficient（q2） value of 0.530 using 6 components, non-cross-validated（r2） value of 0.921 with estimated F value of 93.668, and standard error of estimate（SEE） of 0.185. The best Co MSIA model resulted in q2 = 0.592, r2 = 0.945, N = 10, SEE = 0.162, and F = 75.654, based on steric, electrostatic, hydrophobic and hydrogen bond acceptor fields. The predictive ability of the Co MFA and CoM SIA models was further validated using a test set of 18 molecules that were not included in the training set, which resulted in predictive correlation coefficients（r2pred） of 0.551 and 0.637, respectively. Moreover, the CoM FA and CoM SIA contour maps identified the features important for exhibiting potent binding affinities on NOP, and can thus serve as a useful guide for the design of potential NOP agonists.
文摘Objectives To observe the expression of β3-adrenoceptor （β3-AR） of left ventricle and the effect on heart function by stimulating β3-AR in rats with experimental heart failure. Methods Rats were randomly divided into heart failure group and control group. Heart failure models were built up by ligating coronary artery in rats. The expression of β3-AR mRNA were detected with RT-PCR; The change of heart function were observed after administration of BRL37344 （β3-AR agonist） by measuring left ventricular end-systolic pressure （LVESP）, left ventricular end-diastolic pressure （LVEDP）, the maximum pressure ascending rate of left ventricle （＋dp/ dtmax） and the maximum pressure descending rate of left ventricle（-dp/dtmax）. Results The expression of β3-AR mRNA （β3/β-actin） was 0.028±0.005 and the proportion of β3-AR （β3/β1＋β2＋β3） was 5.4%±0.06% in failure rats while the expression of β3-AR mRNA was 0.011 ±0.004 and the proportion was 1.2%±0.04% in control rats; The descending percentage of LVESP, ＋ dp/dtmax and -dp/dtmax were 16.1%, 21.7% and 13.2% respectively with administration of BRL37344 in failure rats, while 12.2%, 15.8% and 11.5% in control rats. Conclusions Compared with control group the expression of β3-AR mRNA of left ventricle was obviously increased and the negative inotropic function with exciting β3-AR was obviously enhanced in failure groups.
