Tricyclic oxazolo[2,3-f]purinediones: potency as adenosine receptor ligands and anticonvulsants

Bioorganic & Medicinal Chemistry
Anna DrabczyńskaK Kieć-Kononowicz

Abstract

Synthesis and physicochemical properties of 7-mono- and 6,7-disubstituted dihydrooxazolo-[3,2-f]purinediones are described. Oxazolo[2,3-f]purinediones were synthesized by cyclization of 8-bromotheophylline with oxiranes. The obtained compounds (1-22) were evaluated for their affinity at adenosine A(1) and A(2A) receptors. They showed mainly adenosine A(2A) receptor affinity at low micromolar concentrations and A(2A) selectivity, for example, compound 9 with an octyl substituent at the oxazole ring displayed adenosine A(2A) receptor affinity (K(i)=0.998 microM) and at least 25-fold A(2A) versus A(1) selectivity. This compound was less selective (5-fold) towards human recombinant A(2B) and A(3) adenosine receptors. In this group of compounds active adenosine A(1) receptor antagonists were also identified. Oxazolopurinediones were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (ip). Compounds with long alkyl chains showed anticonvulsant activity in both tests (in 100 and 300 mg/kg doses), accompanied by significant neurotoxicity. The anticonvulsant activity in rats (po) was higher and without signs of neurotoxicity. SAR and QSAR studies stressed the importance of lipophilic 7-sub...Continue Reading

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May 17, 2003·European Journal of Medicinal Chemistry·Anna DrabczyńskaKatarzyna Kieć-Kononowicz

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Citations

Jan 26, 2007·European Journal of Pharmacology·Tadeusz LibrowskiMichael Gütschow
Apr 8, 2010·Journal of Separation Science·Piotr KawczakRoman Kaliszan
Jan 8, 2011·Archiv der Pharmazie·Anna DrabczyńskaKatarzyna Kieć-Kononowicz
Aug 7, 2019·BMC Chemistry·Saloni Kakkar, Balasubramanian Narasimhan

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