Virus nucleoprotein (NP) is an emerging target for drug development for Influenza. We designed benzamide derivatives as new inhibitors of NP that demonstrate good potency in blocking influenza A. Screening revealed th...Virus nucleoprotein (NP) is an emerging target for drug development for Influenza. We designed benzamide derivatives as new inhibitors of NP that demonstrate good potency in blocking influenza A. Screening revealed that compound 39 was the most potent molecule in the series, exhibiting IC<sub>50</sub> values of 0.46 and 0.27 μM in blocking the replication of H3N2 (A/HK/8/68) and (A/WSN/33) influenza A viral strains. The observed inhibition of viral replication correlated well with cytopathic protection. Furthermore, based on computational analysis and fluorescence microscopy, it was determined that compound 39 inhibited nuclear accumulation by targeting influenza A viral nucleoproteins. Finally, the rodent pharmacokinetic profile of compound 32 displayed half-life of greater than 4 hours and bioavailability greater than 20%, suggesting this class of molecules had drug-like properties.展开更多
AIM:To study the relative efficacy of cisapride, metoclopramide,domperidone,erythromycin and mosapride on gastric emptying(GE)and small intestinal transit(SIT) in morphine treated mice. METHODS:Phenol red marker meal ...AIM:To study the relative efficacy of cisapride, metoclopramide,domperidone,erythromycin and mosapride on gastric emptying(GE)and small intestinal transit(SIT) in morphine treated mice. METHODS:Phenol red marker meal was employed to estimate GE and SIT in Swiss albino mice of either sex.The groups included were control,morphine 1 mg/kg(s.c.15 rain before test meal)alone or with(45 rain before test meal p.o.)cisapride 10 mg/kg,metoclopramide 20 mg/kg, domperidone 20 mg/kg,erythromycin 6 mg/kg and mosapride 20 mg/kg. RESULTS:Cisapride,metoclopramide and mosapride were effective in enhancing gastric emptying significantly(P<0.001) whereas other prokinetic agents failed to do so in normal mice.Metoclopramide completely reversed morphine induced delay in gastric emptying followed by mosapride. Metoclopramide alone was effective when given to normal mice in increasing the SIT.Cisapride,though it did not show any significant effect on SIT in normal mice,was able to reverse morphine induced delay in SIT significantly(P<0.001) followed by metoclopramide and mosapride. CONCLUSION:Metoclopramide and cisapride are most effective in reversing morphine-induced delay in gastric emptying and small intestinal transit in mice respectively.展开更多
The structureaffinity correlations of a series of benzamides for dopamine D 2 receptor imaging agents have been studied with SYBYL 6.4 software on SGI O 2 workstation.The results of conformational analysis and PM3 cal...The structureaffinity correlations of a series of benzamides for dopamine D 2 receptor imaging agents have been studied with SYBYL 6.4 software on SGI O 2 workstation.The results of conformational analysis and PM3 calculation have demonstrated that the coplanar effect of benzamides is one of the most important requirements for activity in vitro.The aromatic substituent in the 2 position is the main factor which influences the coplanar arrangement of pseudring (B) involving the amide moiety and the methoxy group relative to the aromatic ring,while the influences of other factors on this side such as the aromatic substituents in the 3 and 5 positions and the conformation of side chain may be neglected.The conclusion may be useful in understanding the interaction of D 2 receptorligand and designing new D 2 receptor ligands.展开更多
文摘Virus nucleoprotein (NP) is an emerging target for drug development for Influenza. We designed benzamide derivatives as new inhibitors of NP that demonstrate good potency in blocking influenza A. Screening revealed that compound 39 was the most potent molecule in the series, exhibiting IC<sub>50</sub> values of 0.46 and 0.27 μM in blocking the replication of H3N2 (A/HK/8/68) and (A/WSN/33) influenza A viral strains. The observed inhibition of viral replication correlated well with cytopathic protection. Furthermore, based on computational analysis and fluorescence microscopy, it was determined that compound 39 inhibited nuclear accumulation by targeting influenza A viral nucleoproteins. Finally, the rodent pharmacokinetic profile of compound 32 displayed half-life of greater than 4 hours and bioavailability greater than 20%, suggesting this class of molecules had drug-like properties.
文摘AIM:To study the relative efficacy of cisapride, metoclopramide,domperidone,erythromycin and mosapride on gastric emptying(GE)and small intestinal transit(SIT) in morphine treated mice. METHODS:Phenol red marker meal was employed to estimate GE and SIT in Swiss albino mice of either sex.The groups included were control,morphine 1 mg/kg(s.c.15 rain before test meal)alone or with(45 rain before test meal p.o.)cisapride 10 mg/kg,metoclopramide 20 mg/kg, domperidone 20 mg/kg,erythromycin 6 mg/kg and mosapride 20 mg/kg. RESULTS:Cisapride,metoclopramide and mosapride were effective in enhancing gastric emptying significantly(P<0.001) whereas other prokinetic agents failed to do so in normal mice.Metoclopramide completely reversed morphine induced delay in gastric emptying followed by mosapride. Metoclopramide alone was effective when given to normal mice in increasing the SIT.Cisapride,though it did not show any significant effect on SIT in normal mice,was able to reverse morphine induced delay in SIT significantly(P<0.001) followed by metoclopramide and mosapride. CONCLUSION:Metoclopramide and cisapride are most effective in reversing morphine-induced delay in gastric emptying and small intestinal transit in mice respectively.
文摘The structureaffinity correlations of a series of benzamides for dopamine D 2 receptor imaging agents have been studied with SYBYL 6.4 software on SGI O 2 workstation.The results of conformational analysis and PM3 calculation have demonstrated that the coplanar effect of benzamides is one of the most important requirements for activity in vitro.The aromatic substituent in the 2 position is the main factor which influences the coplanar arrangement of pseudring (B) involving the amide moiety and the methoxy group relative to the aromatic ring,while the influences of other factors on this side such as the aromatic substituents in the 3 and 5 positions and the conformation of side chain may be neglected.The conclusion may be useful in understanding the interaction of D 2 receptorligand and designing new D 2 receptor ligands.
