Noncataleptogenic, centrally acting dopamine D-2 and serotonin 5-HT2 antagonists within a series of 3-substituted 1-(4-fluorophenyl)-1H-indoles

J Med Chem. 1992 Mar 20;35(6):1092-101. doi: 10.1021/jm00084a014.


A series of 1-(4-fluorophenyl)-1H-indoles substituted at the 3-position with 1-piperazinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperidinyl was synthesized. Within all three subseries potent dopamine D-2 and serotonin 5-HT2 receptor affinity was found in ligand binding studies. Quipazine-induced head twitches in rats were inhibited by most derivatives as a measure of central 5-HT2 receptor antagonism. Piperazinyl and tetrahydropyridyl indoles were cataleptogenic, while piperidyl substituted indoles surprisingly were found to be noncataleptogenic or only weakly cataleptogenic. Noncataleptogenic piperidyl derivatives also failed to block dopaminergic-mediated stereotypies, that is methyl phenidate-induced gnawing behavior in mice. These profiles resemble that of the atypical neuroleptic clozapine. 1-Ethyl-2-imidazolidinone was found to be the optimal substituent of the basic nitrogen atom in order to avoid catalepsy. The atypical neuroleptic 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl] ethyl]-2-imidazolidinone (sertindole, compound 14c) was selected for further development as a result of these structure/activity studies.

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / pharmacology
  • Dopamine Antagonists*
  • Imidazoles / chemical synthesis
  • Imidazoles / pharmacology
  • Indoles / chemical synthesis*
  • Indoles / pharmacology
  • Male
  • Mice
  • Piperazines / chemical synthesis
  • Piperazines / pharmacology
  • Quipazine / antagonists & inhibitors
  • Rats
  • Rats, Inbred Strains
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism
  • Serotonin Antagonists / chemical synthesis*
  • Serotonin Antagonists / pharmacology
  • Structure-Activity Relationship


  • Antipsychotic Agents
  • Dopamine Antagonists
  • Imidazoles
  • Indoles
  • Piperazines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Quipazine
  • sertindole