Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes

Bioorg Med Chem Lett. 2021 Jan 1:31:127681. doi: 10.1016/j.bmcl.2020.127681. Epub 2020 Nov 12.

Abstract

In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D2/D3/5-HT1A/5-HT2A receptors and weak α1 and H1 receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.

Keywords: 5-HT receptor; Antipsychotic; DA receptor; H(1) receptor; α(1) Receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemical synthesis
  • Amines / chemistry
  • Amines / pharmacology*
  • Animals
  • Antipsychotic Agents / chemical synthesis
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology*
  • Azepines / chemical synthesis
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Cyclohexanes / chemical synthesis
  • Cyclohexanes / chemistry
  • Cyclohexanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Locomotion / drug effects
  • Molecular Docking Simulation
  • Molecular Structure
  • Receptors, Dopamine / metabolism*
  • Receptors, Serotonin / metabolism*
  • Structure-Activity Relationship

Substances

  • Amines
  • Antipsychotic Agents
  • Azepines
  • Cyclohexanes
  • Receptors, Dopamine
  • Receptors, Serotonin
  • Cyclohexane