Imidazo[1,2-a]pyrazin-8-amine core for the design of new adenosine receptor antagonists: Structural exploration to target the A 3 and A 2A subtypes

Eur J Med Chem. 2017 Jan 5;125:611-628. doi: 10.1016/j.ejmech.2016.09.076. Epub 2016 Sep 26.

Abstract

The imidazo[1,2-a]pyrazine ring system has been chosen as a new decorable core skeleton for the design of novel adenosine receptor (AR) antagonists targeting either the human (h) A3 or the hA2A receptor subtype. The N8-(hetero)arylcarboxyamido substituted compounds 4-14 and 21-30, bearing a 6-phenyl moiety or not, respectively, show good hA3 receptor affinity and selectivity versus the other ARs. In contrast, the 8-amino-6-(hetero)aryl substituted derivatives designed for targeting the hA2A receptor subtype (compounds 31-38) and also the 6-phenyl analogues 18-20 do not bind the hA2A AR, or show hA1 or balanced hA1/hA2A AR affinity in the micromolar range. Molecular docking of the new hA3 antagonists was carried out to depict their hypothetical binding mode to our refined model of the hA3 receptor. Some derivatives were evaluated for their fluorescent potentiality and showed some fluorescent emission properties. One of the most active hA3 antagonists herein reported, i.e. the 2,6-diphenyl-8-(3-pyridoylamino)imidazo[1,2-a]pyrazine 29, tested in a rat model of cerebral ischemia, delayed the occurrence of anoxic depolarization caused by oxygen and glucose deprivation in the hippocampus and allowed disrupted synaptic activity to recover.

Keywords: Adenosine receptor antagonists; Bicyclic heteroaromatic systems; G protein-coupled receptors; Imidazopyrazines; Ligand-receptor modeling studies.

MeSH terms

  • Adenosine A3 Receptor Antagonists / chemistry
  • Adenosine A3 Receptor Antagonists / pharmacology
  • Amines / chemical synthesis*
  • Amines / chemistry
  • Amines / pharmacology
  • Animals
  • Brain Ischemia / drug therapy
  • Chromosome Pairing / drug effects
  • Drug Design*
  • Hippocampus / drug effects
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Molecular Docking Simulation
  • Purinergic P1 Receptor Antagonists / chemical synthesis*
  • Purinergic P1 Receptor Antagonists / chemistry
  • Purinergic P1 Receptor Antagonists / pharmacology
  • Purinergic P1 Receptor Antagonists / therapeutic use
  • Pyrazines / chemical synthesis*
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Rats
  • Receptor, Adenosine A2A / chemistry*
  • Receptor, Adenosine A3 / chemistry*

Substances

  • Adenosine A3 Receptor Antagonists
  • Amines
  • Imidazoles
  • Purinergic P1 Receptor Antagonists
  • Pyrazines
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A3
  • imidazo(1,5-a)pyrazine