Abstract
With the aim to develop new potent and selective ligands of 5-HT(3)-type serotonin receptors and to acquire more information on their structure-affinity relationships, new thieno[2,3-d]pyrimidine derivatives 32-39 were synthesized and their binding to 5-HT(3) versus 5-HT(4 )receptors was studied. Some of these new compounds exhibit good affinity for cortical 5-HT(3) receptors, but not for 5-HT(4) receptors. Among these derivatives, 6-ethyl-4-(4-methyl-1-piperazinyl)-2-(methylthio)thieno[2,3-d]pyrimidine 32 is the most potent ligand (K(i) = 67 nM); it behaves as a competitive antagonist of the 5-HT(3) receptor function in the guinea pig colon. Its binding interactions with 5-HT(3A )receptors were analysed by using receptor modelling and comparative docking.
MeSH terms
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Animals
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Binding, Competitive
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Brain / metabolism
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Colon / drug effects
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Colon / physiology
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Guinea Pigs
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In Vitro Techniques
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Isometric Contraction / drug effects
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Ligands
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Male
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Models, Molecular
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Radioligand Assay
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Rats
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Receptors, Serotonin, 5-HT3 / metabolism*
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Receptors, Serotonin, 5-HT4 / metabolism
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Serotonin 5-HT3 Receptor Antagonists
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Serotonin 5-HT4 Receptor Antagonists
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / pharmacology
Substances
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6-ethyl-4-(4-methyl-1-piperazinyl)-2-(methylthio)thieno(2,3-d)pyrimidine
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Ligands
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Pyrimidines
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Receptors, Serotonin, 5-HT3
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Serotonin 5-HT3 Receptor Antagonists
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Serotonin 5-HT4 Receptor Antagonists
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Thiophenes
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Receptors, Serotonin, 5-HT4