Design, synthesis and binding properties of novel and selective 5-HT3 and 5-HT4 receptor ligands

Eur J Med Chem. 2001 Mar;36(3):287-301. doi: 10.1016/s0223-5234(01)01216-8.

Abstract

This work reports the synthesis and the binding tests on the 5-HT3 and 5-HT4 receptors of new thienopyrimidopiperazine and piperazinylacylaminodimethylthiophene derivatives, in order to identify potent and selective ligands for each receptor. The 3-amino-2-(4-benzyl-1-piperazinyl)-5,6-dimethyl-thieno[2,3-d]pyrimidin-4(3H)-one derivative 28 showed the highest affinity and selectivity for the 5-HT3 over the 5-HT4 receptor (5-HT3 Ki=3.92 nM, 5-HT4 not active), whereas the 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butanoylamino]-4,5-dimethyl-3-thiophenecarboxylic acid ethyl ester (41) showed the highest affinity and selectivity for the 5-HT4 over the 5-HT3 receptor (5-HT4 Ki=81.3 nM, 5-HT3 not active). Conformational analyses were carried out on the compounds of the piperazinylacylaminodimethylthiophene series (39-42) taking compound 41 as the template.

Publication types

  • Corrected and Republished Article

MeSH terms

  • Animals
  • Cricetinae
  • Drug Design
  • Inhibitory Concentration 50
  • Ligands
  • Models, Molecular*
  • Piperazines / chemistry*
  • Piperazines / metabolism*
  • Protein Conformation
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism*
  • Rats
  • Receptors, Serotonin / chemistry
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin, 5-HT3
  • Receptors, Serotonin, 5-HT4
  • Structure-Activity Relationship
  • Thiophenes / chemistry*
  • Thiophenes / metabolism*

Substances

  • 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butanoylamino)-4,5-dimethyl-3-thiophenecarboxylic acid ethyl ester
  • 3-amino-2-(4-benzyl-1-piperazinyl)-5,6-dimethyl-thieno(2,3-d)pyrimidin-4(3H)-one
  • Ligands
  • Piperazines
  • Pyrimidines
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Thiophenes
  • Receptors, Serotonin, 5-HT4