Imidazo[2,1-i]purin-5-ones and Related Tricyclic Water-Soluble Purine Derivatives:  Potent A_2A- and A₃-Adenosine Receptor Antagonists

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.

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

“…The most potent compound at A 2A AR in this series was enantiomerically pure (S)-1,4-dimethyl-8-ethyl-2- styryl-imidazo[2,1-i]purinone (43) possessing enhanced water solubility in comparison with corresponding xanthine derivatives (Fig. (10)) [74]. Compounds envisaged as constrained bioisosteric analogs of 8-styrylxanthines were designed, e.g.…”

Triamino derivatives of triazolotriazine and triazolopyrimidine as adenosine A2a receptor antagonists

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Adenosine A2A receptor contributes to the anti-inflammatory effect of the fixed herbal combination STW 5 (Iberogast®) in rat small intestinal preparations

“…The radioligand binding assays were performed according to methods established by Klotz et al (1989), and Müller (2000), and Müller et al (2002). All studies were carried out as competition assays.…”