title: Tricyclic oxazolo[2,3-f]purinediones: potency as adenosine receptor ligands and anticonvulsants.
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-substituents for both types of pharmacological activity. The volume of the substituent is, however, limited at the A(2A) AR, an n-octyl group being optimal.
authors.affiliation: Jagiellonian University Medical College, Faculty of Pharmacy, Department of Chemical Technology of Drugs, Medyczna 9, Pl 30-688 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Drabczyńska
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Britta
authors.initials: B
authors.lastname: Schumacher
authors.forename: Sonja
authors.initials: S
authors.lastname: Hinz
authors.forename: Janina
authors.initials: J
authors.lastname: Karolak-Wojciechowska
authors.forename: Barbara
authors.initials: B
authors.lastname: Michalak
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Pekala
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011485:Protein Binding / Q000502:physiology; D011687:Purines / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D008024:Ligands; D010080:Oxazoles; D011687:Purines; D018047:Receptors, Purinergic P1