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| - Novel Potent and Selective Central 5-HT3 Receptor Ligands Provided withDifferent Intrinsic Efficacy. 1. Mapping the Central 5-HT3 Receptor BindingSite by Arylpiperazine Derivatives
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| - Synthesis and pharmacological evaluation of a series ofcondensed quinoline and pyridinederivatives bearing a N-methylpiperazine moiety attached tothe 2-position of the quinoline orpyridine nucleus are described. 5-HT receptor binding studiesrevealed subnanomolar affinityfor the 5-HT3 receptor subtype in some of the compoundsunder study. The most activecompound (5b) displayed a Ki valueabout 1 order of magnitude higher than that of quipazinealong with a higher selectivity. The potential 5-HT3agonist/antagonist activity of four selectedcompounds was assessed in vitro on 5-HT3 receptor-dependent[14C]guanidinium uptake inNG 108-15 cells. Compound 5j acted as a5-HT3 agonist in this assay with an EC50 valuecloseto that reported for quipazine, while 5b was a partialagonist with an EC50 value of about 0.25nM, and compound 5c possessed antagonist properties with anIC50 value (≈8 nM) in the samerange as those of previously characterized 5-HT3 receptorantagonists. Qualitative andquantitative structure−affinity relationship studies carried out bymaking use of theoreticalmolecular descriptors allowed to elucidate the role of the mainpharmacophoric componentsand to develop a model for the interaction of the 5-HT3ligands related to quipazine with theirreceptor.
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