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151.
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A series of substituted aryl amide derivatives of 6-naltrexamine, 3 designed to be metabolically stable were synthesized and used to characterize the structural requirements for their potency to binding and functional activity of human mu (μ), delta (δ) and kappa (κ) opioid and nociceptin (NOP) receptors. Binding assays showed that 4–10 had subnanomolar Ki values for μ and κ opioid receptors. Functional assays for stimulation of [35S]GTPγS binding showed that several compounds acted as partial or inverse agonists and antagonists of the μ and δ, κ opioid or NOP receptors. The compounds showed considerable stability in the presence of rat, mouse or human liver preparations and NADPH. The inhibitory activity on the functional activity of human cytochrome P450s was examined to determine any potential inhibition by 4–9. Only modest inhibition of CYP3A4, CYP2C9 and CYP2C19 was observed for a few of the analogs. As a representative example, radiolabeled 6 was examined in vivo and showed reasonable brain penetration. The inhibition of ethanol self-administration in rats trained to self-administer a 10% (w/v) ethanol solution, utilizing operant techniques showed 5–8 to have very potent efficacy (ED50 values 19–50 μg/kg). 相似文献
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Evolutionary conservation of the immediate-early gene ZENK 总被引:3,自引:0,他引:3
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Thirty patients were treated with glibenclamide for periods up to 16 months. The drug is a potent hypoglycaemic agent, and taken in a single daily dose controls blood glucose levels over a 24-hour period in maturity onset diabetes. A definite dose-effect relationship exists, and the drug may be used in doses of 5 to 20 mg. daily. There were no appreciable side-effects or toxic effects during the period of study. 相似文献
158.
Eicosanoids evoke the release of amylase and increase cytoplasmic calcium in rat parotid cells 总被引:1,自引:0,他引:1
K W Snowdowne L Rosenoer E Yu J R Cashman 《Biochemical and biophysical research communications》1989,161(1):379-384
The effects of various eicosanoids on cytoplasmic calcium and the release of amylase were examined in isolated rat parotid cells. Arachidonate and several of its metabolites increased amylase release and elevated cytoplasmic calcium. Melittin, a stimulator of arachidonate mobilization, and lyso-phosphatidylcholine also released amylase and elevated calcium. These results suggest that the metabolites of arachidonate may have an important role in amylase secretion. 相似文献
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