Novel neuroprotective compounds for use in Parkinson's disease

Parkinsonism is a neurodegenerative disease that mostly affects elderly people. Monoamine oxidase B (MAO-B) inhibitors have been used in the symptomatic treatment of motor symptoms of parkinsonism. Selective MAO-B inhibitors have also been shown to be neuroprotective agents. Using piperine, a natural alkaloid obtained from black pepper plant as lead compound, we initiated a virtual screen to identify novel selective MAO-B inhibitors. Twenty compounds were tested in several enzyme assays, with compounds 5223890 and 7691778 showing the most potent MAO-B inhibition. MAO-B IC50 for compounds 5223890 and 7691778 were found to be 286 nM and 599 nM, respectively. These compounds were also screened for antioxidant activity in the oxygen radical absorbance capacity (ORAC) assay and both of them have shown a mild to moderate antioxidant capacity which can increase their neuroprotective effects. Pharmacokinetic high-throughput studies using parallel artificial membrane permeability assay (PAMPA) and bovine serum albumin (BSA) binding assays indicated that these compounds will likely cross the blood-brain barrier and will moderately bind to serum albumin. Several studies have shown that the prevalence of mild cognitive impairment in patients with parkinsonism is about 30% .Interestingly, four of the tested compounds showed mild to moderate acetylcholinesterase inhibition activity .Compound F5123-0122 has shown the most potent inhibitory effect on acetylcholinesterase activity (AchE IC50 of 35.2 micro-Molar). These compounds may be useful for treating parkinsonism with comorbid mild cognitive impairment.