تصنيع ودراسة المواصفات والقوى المحركة المخبرية للأدوية المساعدة للدوبامين Synthesis, Characterization and in Vitro Kinetic Study of Dopamine Prodrugs

Date
2016-12-21
Authors
يحيى فؤاد رشيد خواجا
yahya fuad rasheed khawaja
Journal Title
Journal ISSN
Volume Title
Publisher
AL-Quds University
جامعة القدس
Abstract
Parkinson patients have insufficient dopamine in specific regions of the brain, so attempts have been made to replenish the deficiency in the dopamine. Dopamine itself doesn't cross blood brain barrier, but its precursor, levodopa (LD) is actively transported into the CNS and is converted to dopamine in the brain. The bioavailability of LD is less than 10% with only 1% of administered oral levodopa penetrates the brain. Large doses of levodopa are required because much of the drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiac arrhythmias, and hypotension. To minimize the conversion to dopamine (DA) outside the central nervous system (CNS), LD is usually co- administered with peripheral inhibitors of amino acid decarboxylase (carbidopa and benserazide). In spite of that, other central nervous side effects such as dyskinesia, on-off phenomenon and end-of-dose deterioration still remain.Based on DFT calculations a novel dopamine prodrugs for the treatment of Parkinson’s disease that can improve the overall biopharmaceutical profile of the current medications to enhance effectiveness and to ease the use of the medications were synthesized, characterized, in vitro intra-conversion to their parent drugs and in silico pharmacokinetics and toxicity prediction were also studied. The synthesized dopamine prodrugs have a carboxylic group as a hydrophilic moiety and a hydrocarbon skeleton as a lipophilic moiety, where the combination of both groups ensures a moderate hydrophilic lipophilc balance value. The potential prodrugs are expected to give better bioavailability than the parental drug owing to improved absorption. Furthermore, these prodrugs are believed to be more effective than L-dopa because the latter undergoes decarboxylation in the periphery before reaching the blood– brain barrier. Additionally, the synthesized prodrugs can be used in different dosage forms (I.V., S.C., tablets, and others) because of their potential solubility in organic and aqueous media. For dopamine ProD 1 the experimental t½ values in 0.1N HCl, buffer pH 2.2, buffer pH 5.5 and buffer pH 7.4 were 60.3 hours, 54.66 hours, 99.93 hours and 138.13 hours, respectively. Dopamine ProD 2 was readily converted in 0.1N HCl, buffer pH 2.2, pH 5.5 and pH 7.4 with half -life time (t½) of 48.34 hours, 54.22 hours, 131.98 hours and 193.42 hours, respectively. Finally, in silico predicting of physiochemical parameters, ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties, oral bioavailability and BBB permeability for the synthesized prodrugs were studied. The results revealed that no prodrug had a high risk of toxicity, and all the prodrugs showed good pharmacokinetic properties. Moreover, all synthesized dopamine prodrugs were found to obey Lipinski’s rule of five.
Description
Keywords
العلوم الصيدلانية, Pharmaceutical Sciences
Citation