Synthesis and Biological Evaluation of a Series of Substituted N-alkoxyimides and -Amides as Potential Atypical Antipsychotic Agents

J Med Chem. 1991 Mar;34(3):1068-72. doi: 10.1021/jm00107a028.

Abstract

In a continuing program to discover antipsychotic agents with a reduced propensity toward extrapyramidal side-effects, a series of N-alkoxyimides and -amides was prepared. Evaluation of these compounds in vitro revealed affinities for D2, 5HT2 and 5HT1A receptors. Several members of the series displayed a profile indicative of potential antipsychotic activity in preclinical assays. The most potent compound in these assays, 7, also displayed possible effectiveness for the negative symptoms of schizophrenia. The synthesis of these compounds and details of their structure-activity relationships are described.

MeSH terms

  • Amides / chemical synthesis
  • Amides / metabolism
  • Amides / pharmacology*
  • Animals
  • Antipsychotic Agents / chemical synthesis
  • Antipsychotic Agents / metabolism
  • Antipsychotic Agents / pharmacology*
  • Apomorphine / pharmacology
  • Avoidance Learning / drug effects
  • Catalepsy / chemically induced
  • Chemical Phenomena
  • Chemistry
  • Drug Evaluation, Preclinical
  • Imides / chemical synthesis
  • Imides / metabolism
  • Imides / pharmacology*
  • Male
  • Mice
  • Molecular Structure
  • Motor Activity / drug effects
  • Phthalimides / chemical synthesis
  • Phthalimides / metabolism
  • Phthalimides / pharmacology*
  • Piperazines / chemistry
  • Piperazines / metabolism
  • Piperazines / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Receptors, Adrenergic, alpha / metabolism
  • Receptors, Dopamine / metabolism
  • Receptors, Dopamine D2
  • Receptors, Serotonin / metabolism
  • Self Stimulation
  • Social Behavior
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / metabolism
  • Spiro Compounds / pharmacology*
  • Stereotyped Behavior / drug effects
  • Thiazoles / chemistry
  • Thiazoles / metabolism
  • Thiazoles / pharmacology

Substances

  • Amides
  • Antipsychotic Agents
  • Imides
  • Phthalimides
  • Piperazines
  • Receptors, Adrenergic, alpha
  • Receptors, Dopamine
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • Spiro Compounds
  • Thiazoles
  • 8-((3-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)propyl)oxy)-8-azaspiro(4.5)decane-7,9-dione
  • Apomorphine