Structure-activity relationships for the binding of arylpiperazines and arylbiguanides at 5-HT3 serotonin receptors

J Med Chem. 1996 Sep 27;39(20):4017-26. doi: 10.1021/jm9603936.


Arylpiperazines are nonselective agents that bind at 5-HT3 serotonin receptors with moderate to high affinity, whereas 1-phenylbiguanide is a low-affinity but more selective 5-HT3 agonist. In an attempt to enhance the affinity of the latter agent, and working with the assumption that similarities might exist between the binding of the two types of agents, we formulated structure-activity relationships for the binding of the arylpiperazines and then incorporated those substituents, leading to high affinity for the arylpiperazines, into 1-phenylbiguanide. A subsequent investigation examined the structure-activity relationships of the arylbiguanides and identified arylguanidines as a novel class of 5-HT3 ligands. Although curious similarities exist between the structure-activity relationships of the arylpiperazines, arylbiguanides, and arylguanidines, it cannot be concluded that all three series of compounds are binding in the same manner. Furthermore, upon investigating pairs of compounds in the three series, the arylpiperazines behaved as 5-HT3 antagonists (von Bezold-Jarisch assay) whereas the arylbiguanides and arylguanidines acted as 5-HT3 agonists.

MeSH terms

  • Animals
  • Biguanides / chemistry*
  • Biguanides / metabolism*
  • Biguanides / pharmacology
  • Heart Rate / drug effects
  • Male
  • Molecular Structure
  • Muscle Contraction / drug effects
  • Piperazines / chemistry*
  • Piperazines / metabolism*
  • Piperazines / pharmacology
  • Rabbits
  • Rats
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin / physiology
  • Reflex
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / metabolism
  • Serotonin Receptor Agonists / chemistry
  • Serotonin Receptor Agonists / metabolism
  • Structure-Activity Relationship
  • Urinary Bladder / drug effects
  • Urinary Bladder / physiology


  • Biguanides
  • Piperazines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists