Synthesis And Characterization Of Brain Penetrant Prodrug Of Neuroprotective D264: Potential Disease Modifying Treatment Agent For Parkinsonu27s Disease

摘要

Parkinsonu27s disease (PD) is a complex neurodegenerative disorder with progressive loss of dopamanergic neurons in the substantia nigra region of the brain and accumulation of intracytoplasmic inclusions called `Lewy bodiesu27. PD is characterized by tremors, rigidity, slowness of movement, bradykinesia and postural imbalances. Although the etiology of PD is not well understood, it is well established that oxidative stress, mitochondrial dysfunction, alpha-synuclein aggregation play a central role in the pathogenesis of PD. Current treatment methods are based on symptomatic relief without addressing the underlying pathophysiological factors responsible for the disease. It is important to develop therapies which can address these complex pathogenesis of the disease process and providing symptomatic relief as well. Towards development of novel multifunctional dopamine D2/D3 agonist drugs for the treatment of Parkinsonu27s disease (PD), D-264 was previously synthesized in our lab. D-264, a potent D3 preferring agonist, is one of our lead compounds which showed high neuroprotection in MPTP u26 Lactacystin PD animal models. However, this drug seems to have minimal brain penetration. In order to further enhance the efficacy and bio-availability of D-264 in the brain, we have designed a cysteine based D-264 prodrug as a substantial amount of research points out an important role of antioxidants such as L-cysteine in reducing the oxidative stress associated with PD .To this end, we have evaluated the ex vivo hydrolysis pattern of synthesized prodrug to yield active D-264 in brain u26 plasma solutions using RP-HPLC. In order to evaluate the efficiency of prodrug in crossing blood-brain barrier, in vivo brain penetration studies were performed and efficiency of hydrolysis was quantified using RP-HPLC. Further, DPPH based anti-oxidant assay was performed to evaluate the anti-oxidant property of prodrug. Details of prodrug design, synthesis and pharmacological evaluation will be presented. This work is supported by NS047198 (AD)