New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation

Bioorg Med Chem. 2003 Apr 3;11(7):1493-502. doi: 10.1016/s0968-0896(02)00557-6.

Abstract

The syntheses and biological evaluation of a series of novel indeno[1,2-d]thiazole derivatives are described. Several groups reported 5-HT(3) receptor agonists which were mainly evaluated for their activities on the von Bezold-Jarisch reflex (B-J reflex). We discovered that tetrahydrothiazolopyridine derivative 1b had a contractile effect on the isolated guinea pig colon with weak B-J reflex. Our efforts to find a new type of 5-HT(3) receptor agonists on the isolated guinea pig colon focused on the synthesis of a fused thiazole derivative 1d modified from 1b and reverse-fused thiazole derivatives (7-10). In this series, 10f (YM-31636) showed high affinity and selectivity for the cloned human 5-HT(3) receptor; furthermore, it showed potent and selective 5-HT(3) receptor agonistic activity. YM-31636 was examined for its effects on defecation in animals, thus evaluating the compound as an agent against constipation.

MeSH terms

  • Animals
  • Cathartics / chemical synthesis*
  • Cathartics / pharmacology*
  • Cloning, Molecular
  • Colon / drug effects
  • Constipation / drug therapy*
  • Defecation / drug effects
  • Ferrets
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Magnetic Resonance Spectroscopy
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Radioligand Assay
  • Rats
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin, 5-HT3
  • Recombinant Proteins / metabolism
  • Reflex / drug effects
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / pharmacology*
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacology*

Substances

  • Cathartics
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Recombinant Proteins
  • Serotonin Receptor Agonists
  • Thiazoles