Design, synthesis and preliminary bioactivity evaluation of bitopic benzopyranomorpholine analogues as selective dopamine D3 receptor ligands as anti-drug addiction therapeutic agents

Bioorg Med Chem Lett. 2021 Sep 15:48:128269. doi: 10.1016/j.bmcl.2021.128269. Epub 2021 Jul 17.

Abstract

Three series of bitopic benzopyranomorpholine analogues were designed, synthesized, and evaluated as a novel class of selective ligands for the dopamine D3 receptor. Binding affinities of target compounds were determined using the method of radioligand binding assay. Most compounds demonstrated considerable binding affinities and selectivity for D3 receptor. Besides, the compounds were screened for their ability to alleviate withdrawal symptoms of opioid addiction in animal behavioral models. The results showed that compound 20h displayed nanomolar affinity for the D3R, and exhibited anti-drug addiction efficacy in the animal model of of naloxone-induced withdrawal symptoms in morphine-dependent mice.

Keywords: Anti-drug addiction; Binding affinity; Dopamine D3 receptor ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dopamine Antagonists / chemical synthesis
  • Dopamine Antagonists / chemistry
  • Dopamine Antagonists / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Ligands
  • Mice
  • Molecular Structure
  • Morpholines / chemical synthesis
  • Morpholines / chemistry
  • Morpholines / pharmacology*
  • Naloxone
  • Receptors, Dopamine D3 / antagonists & inhibitors*
  • Receptors, Dopamine D3 / metabolism
  • Structure-Activity Relationship
  • Substance Withdrawal Syndrome / drug therapy*
  • Substance Withdrawal Syndrome / metabolism

Substances

  • Dopamine Antagonists
  • Ligands
  • Morpholines
  • Receptors, Dopamine D3
  • Naloxone
  • morpholine