New selective ligands of human cloned melatonin MT 1 and MT 2 receptors

Naunyn-Schmiedeberg's Archives of Pharmacology(2003)

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摘要
Melatonin has a key role in the circadian rhythm relay to periphery organs. Melatonin exerts its multiple roles mainly through two seven transmembrane domain, G-coupled receptors, namely MT 1 or MT 2 receptors. A pharmacological characterization of these human cloned melatonin hMT 1 and hMT 2 receptors stably expressed in HEK-293 or CHO cells is presented using a 2-[ 125 I]-iodo-melatonin binding assay and a [ 35 S]-GTPγS functional assay. Both reference compounds and new chemically diverse ligands were evaluated. Binding affinities at each receptor were found to be comparable on either HEK-293 or CHO cell membranes. Novel non-selective or selective hMT 1 and hMT 2 ligands are described. The [ 35 S]-GTPγS functional assay was used to define the functional activity of these compounds which included partial, full agonist and/or antagonist activity. None of the compounds acted as an inverse agonist. We report new types of selective antagonists, such as S 25567 and S 26131 for MT 1 and S 24601 for MT 2 . These studies brought other new molecular tools such as the selective MT 1 agonist, S 24268, as well as the non-selective antagonist, S 22153. Finally, we also discovered S 25150, the most potent melatonin receptor agonist, so far reported in the literature.
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关键词
Melatonin,Melatonin receptors,Selective agonists,Selective antagonists
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