Synthesis and Antidopaminergic Activity of Some 3-(aminomethyl)tetralones as Analogues of Butyrophenone

J Med Chem. 1991 Jul;34(7):2242-7. doi: 10.1021/jm00111a046.

Abstract

Starting from beta-benzoylpropionic acid we synthesized 3-(aminomethyl)tetralones in which the amino substituent was 4-(N-piperazinyl)-p-fluorobutyrophenone, 4-benzoylpiperidine, 4-hydroxy-4-phenylpiperidine or 4-(o-methoxyphenyl)piperazine. The possible dopamine antagonist activity of these compounds was investigated in both "in vitro" and "in vivo" experiments. These compounds potently inhibited [3H]spiperone binding to D2 striatal receptors and moderately inhibited [3H]SCH-23390 binding to D1 striatal receptors (Kis in the nanomolar and micromolar ranges, respectively). Apomorphine-induced stereotypies and amphetamine group toxicity were antagonized, to different extents, by the compounds under study, with a potency similar to that of haloperidol. Interestingly, no catalepsy was observed after administration of the new compounds (2-8 mg/kg). The most active compounds "in vivo" 14 and 15 possessed two butyrophenone pharmacophores. However, the tetralone moiety appeared not critical for their antidopaminergic activity, since all target compounds were less active than haloperidol. These studies provide a pharmacological basis for future research on these new compounds devoid of cataleptogenic activity.

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / metabolism
  • Antipsychotic Agents / toxicity
  • Butyrophenones / chemical synthesis*
  • Chemical Phenomena
  • Chemistry
  • Dopamine Antagonists*
  • Male
  • Mice
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Rats
  • Rats, Inbred Strains
  • Receptors, Dopamine / drug effects
  • Receptors, Dopamine / metabolism
  • Stereotyped Behavior / drug effects
  • Structure-Activity Relationship

Substances

  • Antipsychotic Agents
  • Butyrophenones
  • Dopamine Antagonists
  • Receptors, Dopamine