Novel selective and partial agonists of 5-HT3 receptors. Part 1. Synthesis and biological evaluation of piperazinopyrrolothienopyrazines

J Med Chem. 1996 May 10;39(10):2068-80. doi: 10.1021/jm950543x.


A series of piperazinopyrrolo[1,2-a]thieno[3,2-e]- and -[2,3-e]pyrazine derivatives were prepared and evaluated in order to determine the necessary requirements for high affinity on the 5-HT3 receptors and high selectivity versus other 5-HT receptor subtypes. Various substitutions on the piperazine and the thiophene ring of the pyrrolothienopyrazine moieties were systematically explored as well as replacement of the piperazine by other cyclic amines. The best compounds are in the nanomolar range of affinity of 5-HT3 receptors with high to very high selectivity (up to 10,000 for 14b). These high-affinity compounds have in common a benzyl- or allylpiperazine substituent with no substitutions on the thiophene ring. Five of these compounds (1a, 4b, 13a,b, and 14b) have been evaluated on the Von Bezold-Jarisch reflex and were characterized as partial agonists. One of them, 13a, has shown in vivo at very low dose a potent anxiolytic-like activity in the light/dark test.

MeSH terms

  • Animals
  • Cattle
  • Choroid Plexus / metabolism
  • Frontal Lobe / metabolism
  • Hippocampus / metabolism
  • In Vitro Techniques
  • Magnetic Resonance Spectroscopy
  • Male
  • Pyrazines / chemical synthesis*
  • Pyrazines / chemistry
  • Pyrazines / metabolism
  • Pyrazines / pharmacology
  • Rats
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin, 5-HT3
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / chemistry
  • Serotonin Receptor Agonists / metabolism
  • Serotonin Receptor Agonists / pharmacology
  • Swine


  • Pyrazines
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin Receptor Agonists