Parkinson’s disease (PD) is a chronic neurological disorder resulting from the progressive and irreversible degeneration of dopaminergic neurons in the substantia nigra of the brain, with a consequent deplete of dopamine production (1). Dopamine replacement currently represents the major therapeutic strategy which is administered as L-DOPA, its metabolic precursor, usually, in association with other drugs, such as A2A antagonists. These receptors are co-expressed with dopaminergic D2 receptors in striato-pallidal GABA neurons, where they form heterodimeric complexes able to decrease the D2 affinity for dopamine when the A2A ARs are stimulated (2). The prodrug DP-L-A2AANT (1) was designed with a view to conjugating the beneficial effects against PD obtained by combined action of dopamine and A2A antagonists in CNS. The compound 1 was obtained by coupling dopamine via a succinic spacer to a new A2A antagonist (3), the 7-Amino-5-(aminomethyl)cyclohexylmethyl-amino-2(2-furyl) 1,2,4-triazolo [1,5-a] 1,3,5-triazine (2), through amidic bonds. DP-L-A2AANT 1 was considered as a potential prodrug of both dopamine and the A2AANT 2. The affinity of DP-L-A2AANT 1 and its potential hydrolysis products, were tested on human adenosine A1, A2A, A2B and A3 ARs expressed by CHO cells. Finally, we evaluated the hydrolysis pattern of the prodrug DP-L-A2AANT 1 in water, phosphate buffer, human whole blood and rat brain homogenates. The results suggest the prodrug approach as promising for both early and long term pharmacological treatment of PD.
Conjugation of Dopamine and an A2A Adenosine Receptor Antagonist: a possible approach for the treatment of Parkinson’s Disease.
DALPIAZ, Alessandro;CACCIARI, Barbara;VICENTINI, Chiara Beatrice;PAVAN, Barbara;VINCENZI, Fabrizio;BOREA, Pier Andrea;VARANI, Katia
2012
Abstract
Parkinson’s disease (PD) is a chronic neurological disorder resulting from the progressive and irreversible degeneration of dopaminergic neurons in the substantia nigra of the brain, with a consequent deplete of dopamine production (1). Dopamine replacement currently represents the major therapeutic strategy which is administered as L-DOPA, its metabolic precursor, usually, in association with other drugs, such as A2A antagonists. These receptors are co-expressed with dopaminergic D2 receptors in striato-pallidal GABA neurons, where they form heterodimeric complexes able to decrease the D2 affinity for dopamine when the A2A ARs are stimulated (2). The prodrug DP-L-A2AANT (1) was designed with a view to conjugating the beneficial effects against PD obtained by combined action of dopamine and A2A antagonists in CNS. The compound 1 was obtained by coupling dopamine via a succinic spacer to a new A2A antagonist (3), the 7-Amino-5-(aminomethyl)cyclohexylmethyl-amino-2(2-furyl) 1,2,4-triazolo [1,5-a] 1,3,5-triazine (2), through amidic bonds. DP-L-A2AANT 1 was considered as a potential prodrug of both dopamine and the A2AANT 2. The affinity of DP-L-A2AANT 1 and its potential hydrolysis products, were tested on human adenosine A1, A2A, A2B and A3 ARs expressed by CHO cells. Finally, we evaluated the hydrolysis pattern of the prodrug DP-L-A2AANT 1 in water, phosphate buffer, human whole blood and rat brain homogenates. The results suggest the prodrug approach as promising for both early and long term pharmacological treatment of PD.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
