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

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

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

  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dimerization
  • In Vitro Techniques
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Ligands
  • Muscle Contraction / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • Rabbits
  • Radioligand Assay
  • Receptor, Serotonin, 5-HT1B / metabolism
  • Receptor, Serotonin, 5-HT1D / metabolism*
  • Receptors, Serotonin / metabolism*
  • Saphenous Vein / drug effects
  • Saphenous Vein / physiology
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / chemistry
  • Serotonin Receptor Agonists / pharmacology
  • Structure-Activity Relationship

Substances

  • 4-fluoro-N-(3-(1-methyl-4-piperidinyl)-1H-indol-5-yl)benzamide
  • Benzamides
  • Indoles
  • Ligands
  • Receptor, Serotonin, 5-HT1B
  • Receptor, Serotonin, 5-HT1D
  • Receptors, Serotonin
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin Receptor Agonists
  • serotonin 1F receptor