Synthesis and Assessment of Fused β-Carboline Derivatives as Kappa Opioid Receptor Agonists

ChemMedChem. 2021 Jun 17;16(12):1917-1926. doi: 10.1002/cmdc.202100029. Epub 2021 Mar 18.

Abstract

The synthesis of 5-formyl-6-aryl-6H-indolo[3,2,1-de][1,5] naphthyridine-2-carboxylates by reaction between 1-formyl-9H-β-carbolines and cinnamaldehydes in the presence of pyrrolidine in water with microwave irradiation is described. Pharmacophoric modification of the formyl group offered several new fused β-carboline derivatives, which were investigated for their κ-opioid receptor (KOR) agonistic activity. Two compounds 4 a and 4 c produced appreciable agonist activity on KOR with EC50 values of 46±19 and 134±9 nM, respectively. Moreover, compound-induced KOR signaling studies suggested both compounds to be extremely G-protein-biased agonists. The analgesic effect of 4 a was validated by the increase in tail flick latency in mice in a time-dependent manner, which was completely blocked by the KOR-selective antagonist norBNI. Moreover, unlike U50488, an unbiased full KOR agonist, 4 a did not induce sedation. The docking of 4 a with the human KOR was studied to rationalize the result.

Keywords: beta-carboline; kappa opioid receptor agonist; molecular modeling; nitrogen heterocycle; pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemical synthesis
  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Animals
  • Carbolines / chemical synthesis
  • Carbolines / chemistry
  • Carbolines / pharmacology*
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Narcotic Antagonists / chemical synthesis
  • Narcotic Antagonists / chemistry
  • Narcotic Antagonists / pharmacology*
  • Pain / drug therapy*
  • Receptors, Opioid, kappa / agonists*

Substances

  • Analgesics
  • Carbolines
  • Narcotic Antagonists
  • Receptors, Opioid, kappa