Synthesis and structure-activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists

Bioorg Med Chem. 2013 Dec 15;21(24):7841-52. doi: 10.1016/j.bmc.2013.10.010. Epub 2013 Oct 21.

Abstract

To identify potent dual 5-HT2B and 5-HT7 receptor antagonists, we synthesized a series of novel carbonyl guanidine derivatives and examined their structure-activity relationships. Among these compounds, N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (10) had a good in vitro profile, that is, potent affinity for human 5-HT2B and 5-HT7 receptor subtypes (Ki=1.8 nM and Ki=17.6 nM, respectively) and high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 10 also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered.

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

MeSH terms

  • Dose-Response Relationship, Drug
  • Guanidine / analogs & derivatives*
  • Guanidine / chemistry
  • Guanidine / pharmacology*
  • Humans
  • Molecular Structure
  • Receptor, Serotonin, 5-HT2B / metabolism*
  • Receptors, Serotonin / metabolism*
  • Serotonin Antagonists / chemical synthesis
  • Serotonin Antagonists / chemistry*
  • Serotonin Antagonists / pharmacology*
  • Structure-Activity Relationship

Substances

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