Abstract
We demonstrate here that covalent dimerization of 5-HT 1 ligands is an effective design strategy to modulate affinity and selectivity of 5-HT 1 ligands. This approach was applied to LY-334370, a selective agonist of 5-HT 1F receptor, to generate structurally well-defined divalent molecules. Radioligand binding assays to three cloned 5-HT 1 receptor subtypes (5-HT 1B, 5-HT 1D, 5-HT 1F) demonstrated that the affinity of a series of homologous dimers varied significantly upon exploration of three structural variables (linker length, attachment position, functionality). In particular, the series of C 3-to-C 3 linked dimers derived from a monomer ( 3) showed high binding affinity to 5-HT 1D (for example, K i approximately 0.3 nM for dimer 8) but did not bind to 5-HT 1F ( K i > 0.01 mM), providing >10000-fold subtype selectivity. Results from a functional assay (rabbit saphenous vein contraction) demonstrate that certain dimers are 5-HT 1 receptor agonists.
MeSH terms
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Animals
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Benzamides / chemical synthesis*
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Benzamides / chemistry
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Benzamides / pharmacology
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CHO Cells
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Cricetinae
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Cricetulus
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Dimerization
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In Vitro Techniques
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Ligands
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Muscle Contraction / drug effects
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / physiology
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Rabbits
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Radioligand Assay
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Receptor, Serotonin, 5-HT1B / metabolism
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Receptor, Serotonin, 5-HT1D / metabolism*
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Receptor, Serotonin, 5-HT1F
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Receptors, Serotonin / metabolism*
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Saphenous Vein / drug effects
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Saphenous Vein / physiology
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Serotonin 5-HT1 Receptor Agonists
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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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4-fluoro-N-(3-(1-methyl-4-piperidinyl)-1H-indol-5-yl)benzamide
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Benzamides
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Indoles
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Ligands
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Receptor, Serotonin, 5-HT1B
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Receptor, Serotonin, 5-HT1D
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Receptors, Serotonin
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Serotonin 5-HT1 Receptor Agonists
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Serotonin Receptor Agonists