- Similarities and differences in affinity and binding modes of tricyclic pyrimido- and pyrazinoxanthines at human and rat adenosine receptors
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A new series of 32 pyrimido- and 5 tetrahydropyrazino[2,1-f]purinediones was obtained and evaluated for their adenosine receptors (ARs) affinities. The 1,3-dibutyl derivative of 9-(4-(2-(dimethylamino)ethoxy)phenyl)-6,7,8,9-tetrahydropyrimido[1,2-f]purine
- Szymańska, Ewa,Drabczyńska, Anna,Karcz, Tadeusz,Müller, Christa E.,K?se, Meryem,Karolak-Wojciechowska, Janina,Fruziński, Andrzej,Schabikowski, Jakub,Doroz-P?onka, Agata,Handzlik, Jadwiga,Kie?-Kononowicz, Katarzyna
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- Phenylethyl-substituted pyrimido[2,1-f]purinediones and related compounds: Structure-activity relationships as adenosine A1 and A2A receptor ligands
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The synthesis of N-(un)substituted-phenylalkylpyrimido[2,1-f]purinediones was performed starting with 7-(3-chloropropyl)-8-bromotheophylline and 7-(3-chloropropyl)-8-bromo-1,3-dipropylxanthine. Compounds with unsubstituted or substituted ethylene spacer to an aromatic ring were synthesized. Additionally variations in the spacer-elongation of the linker containing more than two atoms, introduction of a double bond or heteroatoms were performed. Physicochemical properties of the synthesized compounds were described. The obtained compounds envisaged as sterically fixed and configurationally stable analogs of 8-styrylxanthines, were evaluated for their affinity to adenosine A1 and A2A receptors, the receptor subtypes that are predominant in the brain. Selected compounds were also investigated for the affinity to the A2B and A3 receptor subtypes. It was stated that phenylethyl pyrimido[2,1-f]purinediones and their analogs with variations of the ethylene spacer (substituted or extended) exhibit micromolar or submicromolar affinity for A2A ARs (adenosine receptors); for example compound 2Ac with p-hydroxy substituent displayed a Ki value of 0.23 μM at the rat A2A receptor. In comparison to the previously obtained phenyl and benzyl pyrimido[2,1-f]purinediones compounds with a shorter spacer, phenethyl derivatives were optimal for A2A AR. The kind of substituent at the aromatic ring was important for the affinity. Oxygen and nitrogen atoms in the spacer resulted frequently in a slight decrease of the A2A AR affinity, introduction of more heteroatoms into the spacer-in carbamates-caused distinctly negative effect on the activity. In this series of compounds more frequently the adenosine A1 activity was observed, also in submicromolar range as for dipropyl derivative 2Ba with Ki value of 0.62 μM at the rat A2A AR. 3D-QSAR models were developed for the compounds presented in this paper as well as in the previous publications showing activity at adenosine A1 and A2A ARs. It was concluded that for the activity at adenosine A1 and A2A receptors lipophilicity, steric effects along with the molecule's electrostatic surface properties had greatest value. Chosen compounds were evaluated in vivo as anticonvulsants in MES, scMet tests and examined for neurotoxicity. Contrary to previously obtained phenyl and benzyl pyrimido[2,1-f]purinediones, all tested compounds were inactive as anticonvulsants.
- Drabczynska, Anna,Mueller, Christa E.,Schiedel, Anke,Schumacher, Britta,Karolak-Wojciechowska, Janina,Fruzinski, Andrzej,Zobnina, Weronika,Yuzlenko, Olga,Kiec-Kononowicz, Katarzyna
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p. 6956 - 6974
(2008/09/16)
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