The thieno[3,2-c]pyridine and furo[3,2-c]pyridine rings: new pharmacophores with potential antipsychotic activity

J Med Chem. 1989 Jun;32(6):1147-56. doi: 10.1021/jm00126a002.

Abstract

Two new arylpiperazine derivatives, the 4-(1-piperazinyl)thieno- and -furo[3,2-c]pyridine ring systems, have been synthesized and appended via tetramethylene chains to various imide rings. Target compounds from each series were found to have significant activity in the blockade of apomorphine stereotypy and apomorphine-induced climbing, the Sidman avoidance response, and the conditioned avoidance response. In addition, while potent affinity for serotonin 5-HT1 and 5-HT2 receptors was observed for both the thieno- and furo[3,2-c]pyridine derivatives, the interaction of these molecules with the dopamine D2 receptor was weak. Electrophysiological studies of the lead prototypes from each series, involving compounds 22 and 33, indicate these two molecules have distinctively different effects on dopamine neurons in areas A9 and A10. Despite the similarity these molecules share in their behavioral indices of antipsychotic activity, it is likely that the thieno- and furo[3,2-c]pyridine rings employ different mechanisms to achieve this convergence of biological effects.

Publication types

  • Comparative Study

MeSH terms

  • Amphetamines
  • Animals
  • Avoidance Learning / drug effects
  • Binding, Competitive
  • Catalepsy / chemically induced
  • Chemical Phenomena
  • Chemistry
  • Dioxanes / metabolism
  • Female
  • Furans / chemical synthesis
  • Furans / pharmacology
  • Furans / therapeutic use
  • Macaca
  • Male
  • Mice
  • Molecular Structure
  • Motor Activity / drug effects
  • Piperazines* / chemical synthesis
  • Piperazines* / pharmacology
  • Piperazines* / therapeutic use
  • Psychoses, Substance-Induced / drug therapy
  • Psychotic Disorders / drug therapy*
  • Pyridines* / chemical synthesis
  • Pyridines* / pharmacology
  • Pyridines* / therapeutic use
  • Rats
  • Rats, Inbred Strains
  • Receptors, Adrenergic, alpha / metabolism
  • Receptors, Dopamine / metabolism
  • Receptors, Serotonin / metabolism
  • Spiperone / metabolism
  • Stereotyped Behavior / drug effects
  • Structure-Activity Relationship
  • Thiophenes* / chemical synthesis
  • Thiophenes* / pharmacology
  • Thiophenes* / therapeutic use

Substances

  • Amphetamines
  • Dioxanes
  • Furans
  • Piperazines
  • Pyridines
  • Receptors, Adrenergic, alpha
  • Receptors, Dopamine
  • Receptors, Serotonin
  • Thiophenes
  • Spiperone
  • (2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane