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J Med Chem. 2008 Jun 26;51(12):3609-16. doi: 10.1021/jm7011722. Epub 2008 May 29.

Designing selective, high affinity ligands of 5-HT1D receptor by covalent dimerization of 5-HT1F ligands derived from 4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide.

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Department of Medicinal Chemistry, Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, USA.


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.

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