A novel conjugated agent between dopamine and an A2A adenosine receptor antagonists as a potential anti-Parkinson multitarget approach.

We propose a potential antiparkinsonian prodrug DP-L-A2AANT (2) obtained by amidic conjugation of dopamine (1) via a succinic spacer to a new triazolo-triazine A2A adenosine receptor (AR) antagonist A2AANT (3). The affinity of 2 and its hydrolysis products1, 3, dopamine-linker DP-L (4) and A2AANT-linker L-A2AANT (5)was evaluated for hA1, hA2A, hA2B and hA3 ARs and rat striatum A2AARs or D2 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 hA2A affinity was shown by compounds 2 (Ki = 7.32 ± 0.65 nM), 3 (Ki = 35 ± 3 nM) and 5 (Ki = 72 ± 5 nM), whose affinity values were similar in rat striatum. These compounds were not able to change dopamine affinity for D2 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 A2AANT (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.