Alessandro Dalpiaz, Barbara Cacciari, Chiara Beatrice Vicentini, Fabrizio Bortolotti, Giampiero Spalluto, Stephanie Federico, Barbara Pavan, Fabrizio Vincenzi, Pier Andrea Borea, Katia Varani
Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
Molecular pharmaceutics 2012 Mar 5We propose a potential antiparkinsonian prodrug DP-L-A(2A)ANT (2) obtained by amidic conjugation of dopamine (1) via a succinic spacer to a new triazolo-triazine A(2A) adenosine receptor (AR) antagonist A(2A)ANT (3). The affinity of 2 and its hydrolysis products-1, 3, dopamine-linker DP-L (4) and A(2A)ANT-linker L-A(2A)ANT (5)-was evaluated for hA(1), hA(2A), hA(2B) and hA(3) ARs and rat striatum A(2A)ARs or D(2) receptors. The hydrolysis patterns of 2, 4 and 5 and the stabilities of 1 and 3 were evaluated by HPLC analysis in human whole blood and rat brain homogenates. High hA(2A) affinity was shown by compounds 2 (K(i) = 7.32 ± 0.65 nM), 3 (K(i) = 35 ± 3 nM) and 5 (K(i) = 72 ± 5 nM), whose affinity values were similar in rat striatum. These compounds were not able to change dopamine affinity for D(2) receptors but counteracted the CGS 21680-induced reduction of dopamine affinity. DP-L (4) was inactive on adenosine and dopaminergic receptors. As for stability studies, compounds 4 and 5 were not degraded in incubation media. In human blood, the prodrug 2 was hydrolyzed (half-life = 2.73 ± 0.23 h) mainly on the amidic bound coupling the A(2A)ANT (3), whereas in rat brain homogenates the prodrug 2 was hydrolyzed (half-life > eight hours) exclusively on the amidic bound coupling dopamine, allowing its controlled release and increasing its poor stability as characterized by half-life = 22.5 ± 1.5 min.
Alessandro Dalpiaz, Barbara Cacciari, Chiara Beatrice Vicentini, Fabrizio Bortolotti, Giampiero Spalluto, Stephanie Federico, Barbara Pavan, Fabrizio Vincenzi, Pier Andrea Borea, Katia Varani. A novel conjugated agent between dopamine and an A2A adenosine receptor antagonist as a potential anti-Parkinson multitarget approach. Molecular pharmaceutics. 2012 Mar 5;9(3):591-604
PMID: 22292533
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