In the last years numerous studies have confirmed the potential ability of A₁ and A_2A adenosine receptor antagonists to prevent acute renal failure, neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy [1]. Methylxanthines such as theophylline and caffeine have been known to enhance locomotor activity; however, these compounds are nonselective antagonists and have weak affinity for A_2AAR. Potent A_2AAR antagonists were discovered among 8-styrylxanthines: KW-6002 similarly potent to MSX-2, now is in the phase II clinical trials [2-4]. Compounds envisaged as constrained bioisosteric analogues of 8-styrylxanthines, pyrimido[1,2-a]purinediones (1), appeared to be active ligands [5].

To investigate the influence of the additional nitrogen atom and substituents in the annelated cycle series of [1,2,4]triazino- (2) and [1,2,4]triazepino[4,3-f]purinediones (3) were designed, synthesised and investigated in radioligand binding assays: A₁AR affinity - rat cortical membranes using ³[H]CCPA, A_2AAR affinity - rat brain striatal membranes using ³[H]MSX-2. Molecular modelling and SAR studies were performed to investigate structure-activity relationships using programs CAChe 6.1, HyperChem 7.5 and Alchemy2000.

[1,2,4]Triazino[4,3-a]purinediones (2) have shown affinity toward A₁AR. Compounds with C3-phenyl substituent were most active, introduction of N-acyl group has improved selectivity. In turn, N-phenyl derivatives were inactive toward both AR subtypes. The N-unsubstituted analogues in the group of 1,2,4-triazepino[4,3-f]purinediones (3) are A_2AAR ligands, while the N-substituted compounds are A₁AR ligands. The character of the linkage of N-substituent is important for the selectivity while the length is important for affinity. Generally, compounds possessing ethyl moiety at C3-atom of triazepine ring were more active.

The research was partly supported by Polish State Committee for Scientific Research Grant No. 2 PO5F 01428

1. Fredholm, B.B.; Abbrachio, M.P.; Brunstock, G.; Doly, J.W.; Harden, T.K.; Jacobson, K.A.; Leff, B.; Williamo, M. Pharmacol. Rev., 1994, 46, 143.
2. Ongini, E.; Monopoli, A.; Cacciari, B.; Baraldi, P.G. Farmaco. 2001, 56, 87.
3. Chase, T.N.; Bibbiani, F.; Bara-Jimenez, W.; Dimitrowa, T.; Oh-Lee, J.D. Neurology, 2003, 61, 107.
4. Wu, S.S.; Frucht, S.J. CNS Drugs,2005, 19, 723.
5. Drabczyńska, A.; Müller, C.E.; Schumacher, B.; Karolak-Wojciechowska, J.; Michalak, B.; Pękala, E.; Kieć-Kononowicz, K. Eur. J. Med. Chem., 2003, 38, 397.

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1. DETERMIANTION OF LIPOPHILICITY OF THE IMIDAZO-, PYRIMIDO-, AND DIAZEPINOPURINEDIONS - ADENOSINE RECEPTORS LIGANDS
2. HISTAMINE H₃ RECEPTOR ACTIVITY OF 4-N-SUBSTITUTED PIPERAZINE-1-N-ALKYL ETHERS
3. BIOTRANSFORMATION OF PRAZIQUANTEL BY HUMAN CYTOCHROME P450 3A4 (CYP 3A4)
4. NONNATURAL D-AMINO ACIDS AS A BUILDING BLOCKS OF NEW PEPTIDOMIMETICS
5. SEARCHING FOR OPTIMAL METHOD FOR SOLUBILITY PREDICTION AMONG BIOLOGICALLY ACTIVE PHENYLPIPERAZINE DERIVATIVES OF PHENYTOIN
6. LIPOPHILICITY OF ANTITUBERCULOTIC 5-ARYLIDENE DERIVATIVES OF (THIO)HYDANTOIN EVALUATED IN SILICO AND BY MEANS OF RP-TLC
7. THE COMPARATIVE STUDIES ON ADENOSINE RECEPTORS AFFINITY OF PYRIMIDO AND PYRAZINO PURINEDIONES
8. DESIGN AND SYNTHESIS OF HAPTEN TO GENERATE CATALYTIC ANTIBODIES THAT REDUCE PENTOXIFYLLINE
9. SYNTHESIS AND ANTICONVULSANT EVALUATION OF SOME N-ALKENYL / ALKINYL PHTHALIMIDE DERIVATIVES