Synthesis and pharmacological evaluation of 11-(1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-dibenzo[b,e][1,4]diazepines with clozapine-like receptor occupancy at dopamine D1/D2 receptor

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127563. doi: 10.1016/j.bmcl.2020.127563. Epub 2020 Sep 22.

Abstract

Clozapine-like compound without agranulocytosis risk is need to cure the treatment resistant schizophrenia (TRS). We discovered (S)-3 as Clozapine-like dopamine D2/D1 receptor selectivity and improved reactive metabolites formation profile by the modification of piperazine moiety in Clozapine. The optimization of (S)-3 gave compound 5 to be best compound (approximately 10-fold stronger affinity for D2/D1 receptor and similar D2/D1 selectivity ratio with Clozapine). Clozapine-like D2/D1 receptor occupancy profile was proved by in vivo evaluation. In addition, the reactive metabolites derived agranulocytosis risk of compound 5 was considered to be lower than Clozapine. The pharmacology detail of compound 5 is being investigated to develop it for TRS treatment.

Keywords: Agranulocytosis; Antipsychotics; Clozapine; Dopamine; Reactive metabolites; Treatment resistant schizophrenia.

MeSH terms

  • Antipsychotic Agents / chemical synthesis
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology*
  • Azepines / chemical synthesis
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Clozapine / chemistry
  • Clozapine / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Receptors, Dopamine D1 / antagonists & inhibitors*
  • Receptors, Dopamine D2 / metabolism*
  • Schizophrenia / drug therapy*
  • Structure-Activity Relationship

Substances

  • Antipsychotic Agents
  • Azepines
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Clozapine