Phenylethyl-substituted pyrimido[2,1-f]purinediones and related compounds: structure-activity relationships as adenosine A(1) and A(2A) receptor ligands.
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 A(1) and A(2A) receptors, the receptor subtypes that are predominant in the brain. Selected compounds were also investigated for the affinity to the A(2B) and A(3) 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 A(2A) ARs (adenosine receptors); for example compound 2Ac with p-hydroxy substituent displayed a K(i) value of 0.23 microM at the rat A(2A) 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 A(2A) 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 A(2A) 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 A(1) activity was observed, also in submicromolar range as for dipropyl derivative 2Ba with K(i) value of 0.62 microM at the rat A(2A) AR. 3D-QSAR models were developed for the compounds presented in this paper as well as in the previous publications showing activity at adenosine A(1) and A(2A) ARs. It was concluded that for the activity at adenosine A(1) and A(2A) 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.
Drabczyńska
Anna
A
Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, Pl 30-688 Kraków, Poland.
Müller
Christa E
CE
Schiedel
Anke
A
Schumacher
Britta
B
Karolak-Wojciechowska
Janina
J
Fruziński
Andrzej
A
Zobnina
Weronika
W
Yuzlenko
Olga
O
Kieć-Kononowicz
Katarzyna
K
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011687:Purines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000187:drug effects*; D043683:Receptors, Adenosine A2 / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship