Abstract
The synthesis of several novel indole melatonin analogues substituted at the 2-position with acylaminomethyl (8-11), acylaminoethyl (5a-k), or acylaminopropyl (13) side chains is reported. On the basis of a novel in vitro functional assay (specific binding of [35S]GTPgammaS), which can discriminate agonist from partial agonist, antagonist, and inverse agonist ligands, 5a,g, h,j and 13 were shown to be partial agonists, 5d,e and 8-11 competitive antagonists, and 5b,c,k putative inverse agonists. Binding and functional assays were performed on cloned human MT1 receptor. Structure-activity relationship considerations indicate that N-[1-aryl-2-(4-methoxy-1H-indol-2-yl)(C1-C2)alkyl]alkanamides represent a lead structure for this type of ligands.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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GTP-Binding Proteins / metabolism
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Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / metabolism
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Indoles / pharmacology
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Ligands
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Melatonin / metabolism*
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Mice
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Rats
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Receptors, Cell Surface / agonists*
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Receptors, Cell Surface / antagonists & inhibitors*
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Receptors, Cell Surface / biosynthesis
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Receptors, Cell Surface / metabolism
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Melatonin
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Sodium Chloride / metabolism
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Structure-Activity Relationship
Substances
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Indoles
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Ligands
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Receptors, Cell Surface
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Receptors, Cytoplasmic and Nuclear
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Receptors, Melatonin
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Guanosine 5'-O-(3-Thiotriphosphate)
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Sodium Chloride
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GTP-Binding Proteins
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Melatonin