Synthesis and Structure-Activity Relationships of New Carbonyl Guanidine Derivatives as Novel Dual 5-HT₂B and 5-HT₇ Receptor Antagonists. Part 2

Bioorg Med Chem. 2014 Aug 1;22(15):4323-37. doi: 10.1016/j.bmc.2014.05.027. Epub 2014 May 28.


We previously reported that the novel dual 5-HT₂B and 5-HT7 receptor antagonist N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (4) exerted a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs. To develop a synthetic strategy, we performed docking studies of lead compound 4 bound to 5-HT₂B and 5-HT₇ receptors, and observed that the carbonyl guanidine group forms a tight interaction network with an active center Asp (D135:5-HT2B, D162:5-HT₇), Tyr (Y370:5-HT₂B, Y374:5-HT₇) and aromatic residue (W131:5-HT2B, F158:5-HT₇). Based on molecular modeling results, we optimized the substituents at the 5- to 8-position and 9-position of the fluorene ring and identified N-(diaminomethylene)-9-hydroxy-9-methyl-9H-fluorene-2-carboxamide (24a) exhibits potent affinity for 5-HT₂B (Ki=4.3 nM) and 5-HT7 receptor (Ki=4.3 nM) with high selectivity over 5-HT₂A, 5-HT₂C, α₁, D₂ and M₁ receptors. Compound 24a reversed the hypothermic effect of 5-carboxamidotryptamine (5-CT) in mice and also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered at 30 mg/kg. Compound 24a is therefore a promising candidate for a novel class of anti-migraine agent without any adverse effects.

Keywords: 5-HT(2B) receptor; 5-HT(7) receptor; Carbonyl guanidine; Docking study; Dual antagonist; Migraine.

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Body Temperature / drug effects
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Guanidine / analogs & derivatives*
  • Guanidine / chemical synthesis
  • Guanidine / pharmacokinetics
  • Guinea Pigs
  • HEK293 Cells
  • Humans
  • Hypothermia, Induced
  • Male
  • Mice
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptor, Serotonin, 5-HT2B / chemistry*
  • Receptor, Serotonin, 5-HT2B / genetics
  • Receptor, Serotonin, 5-HT2B / metabolism
  • Receptors, Serotonin / chemistry*
  • Receptors, Serotonin / genetics
  • Receptors, Serotonin / metabolism
  • Serotonin / analogs & derivatives
  • Serotonin / pharmacology
  • Serotonin Antagonists / chemical synthesis*
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / pharmacokinetics
  • Structure-Activity Relationship


  • Receptor, Serotonin, 5-HT2B
  • Receptors, Serotonin
  • Serotonin Antagonists
  • serotonin 7 receptor
  • Serotonin
  • 5-carboxamidotryptamine
  • Guanidine