Abstract
Chemical modifications of compound 1 (DR4004), a potent, selective antagonist of the 5-HT(7) receptor, were conducted with the aim of improving its metabolic stability. Halogenation of putative sites of oxidative metabolism afforded compounds 7-10, which retained high affinity and selectivity for the 5-HT(7) receptor, and showed increased in vitro metabolic stability. Compound 10 (DR4485) showed oral bioavailability, and should be a useful tool for evaluating the therapeutic potential of 5-HT(7) antagonists.
MeSH terms
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Animals
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Biological Availability
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Cell Line
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Cyclic AMP / metabolism
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Drug Stability
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Halogens
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Humans
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Indoles / chemical synthesis*
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Pyridines
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Radioligand Assay
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Rats
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Receptors, Serotonin / chemistry*
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Receptors, Serotonin / drug effects
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Serotonin Antagonists / chemical synthesis*
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Serotonin Antagonists / pharmacokinetics
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Serotonin Antagonists / pharmacology
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Structure-Activity Relationship
Substances
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DR-4004
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Halogens
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Indoles
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Pyridines
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Receptors, Serotonin
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Serotonin Antagonists
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serotonin 7 receptor
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Cyclic AMP