Imidazo[2,1-i]purin-5-ones and Related Tricyclic Water-Soluble Purine Derivatives: Potent A(2A)- And A(3)-adenosine Receptor Antagonists

J Med Chem. 2002 Aug 1;45(16):3440-50. doi: 10.1021/jm011093d.

Abstract

A series of tricyclic imidazo[2,1-i]purinones and ring-enlarged analogues derived from xanthine derivatives have been prepared as adenosine receptor (AR) antagonists. In comparison with xanthines, the tricyclic compounds exhibit increased water solubility due to a basic nitrogen atom, which can be protonated under physiological conditions. Substituents were introduced that confer high affinity for A(2A) or A(3) ARs, respectively. A new capillary electrophoresis method was developed for the determination of the enantiomeric purity of selected chiral products using native and modified beta-cyclodextrins as chiral discriminators. The compounds were investigated in radioligand binding assays at rat brain A(1) and A(2A) ARs. Selected compounds were additionally investigated in radioligand binding assays at human recombinant A(3) ARs and in functional studies (adenylate cyclase assays) at A(1) ARs of rat fat cell membranes, A(2A) ARs of rat PC 12 cell membranes, and mouse A(2B) ARs of NIH 3T3 cell membranes. Structure-activity relationships were similar to those of corresponding xanthine derivatives. The 2-styrylimidazopurinones were less potent at A(2A) ARs as compared to 8-styrylxanthine derivatives. The most potent compound at A(2A) ARs was (S)-1,4-dimethyl-8-ethyl-2-styryl-imidazo[2,1-i]purinone (S-25) exhibiting a K(i) value of 424 nM at rat A(2A) ARs. The compound was highly selective for A(2A) receptors vs A(1) and A(3) ARs. Selectivity vs A(2B) ARs, however, was low. Among the 1-unsubstituted 2-phenyl-imidazo[2,1-i]purin-5-one derivatives, very potent and highly selective antagonists for human A(3) ARs were identified. The most potent A(3) antagonist of the present series was (R)-4-methyl-8-ethyl-2-phenyl-imidazo[2,1-i]purin-5-one (R-24) exhibiting a K(i) value of 2.3 nM and high selectivity for A(3) receptors vs all other AR subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adenylyl Cyclase Inhibitors
  • Adenylyl Cyclases / biosynthesis
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Electrophoresis, Capillary
  • Heterocyclic Compounds, 3-Ring / chemical synthesis*
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Membranes
  • Mice
  • PC12 Cells
  • Purinergic P1 Receptor Antagonists*
  • Purines / chemical synthesis*
  • Purines / chemistry
  • Purines / pharmacology
  • Purinones / chemical synthesis*
  • Purinones / chemistry
  • Purinones / pharmacology
  • Radioligand Assay
  • Rats
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A2B
  • Receptor, Adenosine A3
  • Solubility
  • Stereoisomerism
  • Structure-Activity Relationship
  • Water

Substances

  • 1,4-dimethyl-8-ethyl-2-styrylimidazo(2,1-i)purinone
  • 4-methyl-8-ethyl-2-phenylimidazo(2,1-i)purin-5-one
  • Adenylyl Cyclase Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Imidazoles
  • Purinergic P1 Receptor Antagonists
  • Purines
  • Purinones
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A2B
  • Receptor, Adenosine A3
  • Water
  • Adenylyl Cyclases