L-750355, a human ß3-adrenoceptor agonist; in vitro pharmacology and profile of activity in vivo in the rhesus monkey
Michael J. ForrestGary J. HomTom BachMari R. CandeloreMargaret A. CascieriCatherine D. StraderLaurie TotaMichael H. FisherJohn SzumiloskiHyun OkAnn E. WeberMatthew J. WyvrattPasquale P. VicarioO. MarkoLiping DengC CioffeBonnie Hegarty-FriscinoEuan MacIntyre
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We have isolated emetine-resistant cell lines from Chinese hamster peritoneal fibroblasts and have shown that they represent a third distinct class or complementation group of emetine-resistant mutants, as determined by three different criteria. These mutants, like those belonging to the two other complementation groups we have previously defined, which were isolated from Chinese hamster lung and Chinese hamster ovary cells, have alterations that directly affect the protein biosynthetic machinery. So far, there is absolute cell line specificity with respect to the three complementation groups, in that all the emetine-resistant mutants we have isolated from Chinese hamster lung cells belong to one complementation group, all those we have isolated from Chinese hamster ovary cells belong to a second complementation group, and all those isolated from Chinese hamster peritoneal cells belong to a third complementation group. Thus, in cultured Chinese hamster cells, mutations in at least three different loci, designated emtA, emtB, and emtC, encoding for different components of the protein biosynthetic machinery, can give rise to the emetine-resistant phenotype.
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Summary The effect of bioactive agents in many, if not most, cases should be considered as the result of an interaction among molecules of the active agent, the drug, and particular molecular sites of action, receptors (sometimes enzymes), in the biological object. In those cases in which a drug-receptor interaction is involved, two essential parameters should be distinguished, namely, the affinity of the active agent to its receptor, and the intrinsic activity of the active agent, i.e., the capacity to activate the receptors in the process of the drug-receptor interaction. Compounds that have only an affinity to particular types of receptors without an intrinsic activity will behave as blocking agents. Compounds may greatly differ in their affinity. Also, the capacity of bioactive agents to activate their specific receptors, the intrinsic activity, may differ for different compounds. These variations result in a differentiation among full agonists, partial agonists, partial antagonists, and full antagonists, which, besides their affinity to the receptors, display a high, intermediate, low, and zero intrinsic activity, respectively, for the receptors. Examples of partial antagonists are the adrenergic blockers with intrinsic sympathomimetic activity. Various aspects of partial agonists and partial antagonists are discussed and elucidated.
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We have isolated emetine-resistant cell lines from Chinese hamster peritoneal fibroblasts and have shown that they represent a third distinct class or complementation group of emetine-resistant mutants, as determined by three different criteria. These mutants, like those belonging to the two other complementation groups we have previously defined, which were isolated from Chinese hamster lung and Chinese hamster ovary cells, have alterations that directly affect the protein biosynthetic machinery. So far, there is absolute cell line specificity with respect to the three complementation groups, in that all the emetine-resistant mutants we have isolated from Chinese hamster lung cells belong to one complementation group, all those we have isolated from Chinese hamster ovary cells belong to a second complementation group, and all those isolated from Chinese hamster peritoneal cells belong to a third complementation group. Thus, in cultured Chinese hamster cells, mutations in at least three different loci, designated emtA, emtB, and emtC, encoding for different components of the protein biosynthetic machinery, can give rise to the emetine-resistant phenotype.
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