The antiparkinsonian effects of dopamine can be enhanced by the presence of A2A adenosine receptor antagonists in the central nervous system (CNS). We have therefore studied a new prodrug of dopamine (DP) obtained by its amidic conjugation to an A2A antagonist (ANT) via succinic linker (LK). Pharmacokinetic studies of DP, ANT, DP –LK-ANT and its hydrolysis products DP-LK and LK-ANT have been performed in human whole blood and rat brain homogenates. DP-LK and LK-ANT were not degraded in the incubation media. DP was totally degraded in brain homogenates within 3 hours, whereas in human blood it was degraded with a slower rate. ANT was degraded in blood with a rate higher than in brain homogenates. In human blood, the prodrug DP-LK-ANT was hydrolyzed (half-life = 2.73 ± 0.23 h) mainly on the amidic bound coupling ANT, whereas in rat brain homogenates the DP-LK-ANT was hydrolyzed (half-life > eight hours) exclusively on the amidic bound coupling dopamine, allowing the controlled release of DP and increasing its poor stability as characterized by half-life = 22.5 ± 1.5 min. DP-LK-ANT and LK-ANT showed higher affinity toward A2A receptors than ANT. The prodrug DP-LK-ANT appears therefore a carrier of dopamine potentially able to increase its stability and antiparkinsonian effects in the CNS.
Dopamine conjugation with A2A Antagonist: enhancement of drug effect and its controlled release in brain homogenates
DALPIAZ, Alessandro;CACCIARI, Barbara;VICENTINI, Chiara Beatrice;PAVAN, Barbara;VINCENZI, Fabrizio;BOREA, Pier Andrea;VARANI, Katia
2012
Abstract
The antiparkinsonian effects of dopamine can be enhanced by the presence of A2A adenosine receptor antagonists in the central nervous system (CNS). We have therefore studied a new prodrug of dopamine (DP) obtained by its amidic conjugation to an A2A antagonist (ANT) via succinic linker (LK). Pharmacokinetic studies of DP, ANT, DP –LK-ANT and its hydrolysis products DP-LK and LK-ANT have been performed in human whole blood and rat brain homogenates. DP-LK and LK-ANT were not degraded in the incubation media. DP was totally degraded in brain homogenates within 3 hours, whereas in human blood it was degraded with a slower rate. ANT was degraded in blood with a rate higher than in brain homogenates. In human blood, the prodrug DP-LK-ANT was hydrolyzed (half-life = 2.73 ± 0.23 h) mainly on the amidic bound coupling ANT, whereas in rat brain homogenates the DP-LK-ANT was hydrolyzed (half-life > eight hours) exclusively on the amidic bound coupling dopamine, allowing the controlled release of DP and increasing its poor stability as characterized by half-life = 22.5 ± 1.5 min. DP-LK-ANT and LK-ANT showed higher affinity toward A2A receptors than ANT. The prodrug DP-LK-ANT appears therefore a carrier of dopamine potentially able to increase its stability and antiparkinsonian effects in the CNS.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
