Abstract
A series of quinolinecarboxylic acid amides and an ester with a quinuclidine moiety were synthesized and their in vitro affinities at 5-HT3, 5-HT4, and D2 receptors evaluated by radioligand binding assays. Highest affinity at 5-HT3 receptor corresponded to derivative 5 with Ki = 9.9 nM and with selectivity over 5-HT4 and D2 receptors. Compounds displayed moderate 5-HT3 antagonist activity (ED50 = 10.5-21.5 microg/kg i.v.). The obtained data suggest that the 5-HT3 receptor sites can accommodate the acyl group of the 2-quinoline derivatives. The results indicate the existence of an optimal distance between the lone electron pair of the quinoline nitrogen atom and the azabicyclic nitrogen atom, and a no-pharmacophoric pocket in the 5-HT3 receptor which would hold the fragment at the position 4 of the quinoline ring.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Dopamine Antagonists / chemical synthesis
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Dopamine Antagonists / chemistry
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Dopamine Antagonists / pharmacology
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Drug Design
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Guinea Pigs
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Male
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Quinolines / chemical synthesis*
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Quinolines / chemistry
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Quinolines / pharmacology
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Rats
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Rats, Wistar
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Receptors, Dopamine D2 / drug effects
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Receptors, Dopamine D2 / metabolism
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Receptors, Serotonin / drug effects
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Receptors, Serotonin / metabolism*
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Receptors, Serotonin, 5-HT3
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Receptors, Serotonin, 5-HT4
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Serotonin Antagonists / chemical synthesis*
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Serotonin Antagonists / chemistry
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Serotonin Antagonists / pharmacology
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Serotonin Receptor Agonists / chemical synthesis
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Serotonin Receptor Agonists / chemistry
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Serotonin Receptor Agonists / pharmacology
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Structure-Activity Relationship
Substances
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Dopamine Antagonists
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Quinolines
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Receptors, Dopamine D2
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Receptors, Serotonin
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Receptors, Serotonin, 5-HT3
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Serotonin Antagonists
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Serotonin Receptor Agonists
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Receptors, Serotonin, 5-HT4
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quinoline-4-carboxylic acid