A New Type of Prodrug for the Treatment of Parkinson’s Disease
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چکیده
We have discovered a novel type of orally active prodrug of a dopaminergic catecholamine. The prodrug has an enone structure that by an enantioselective bioactivation is converted to the known potent mixed dopamine D1/D2 receptor agonist 5,6-di-OH-DPAT (Figure 2.1). The bioactivation mechanism was found to be selective for 2.3a ((S)-PD148903) which produces the catecholamine (S)-5,6-dihydroxy-2-dipropylaminotetralin, (S)-5,6-di-OHDPAT. This metabolite was detected in the blood and in the brain of rats treated with 2.3a. In rats treated with PD217016 ((R)-PD148903) the corresponding catecholamine could be detected in the blood but not in the brain. This indicates an enantioselective delivery (S)-5,6-di-OHDPAT to the CNS. Orally administered 2.3a proved to be efficacious in the Ungerstedt rat model for Parkinson’s disease.
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