title: Synthesis and characterization of brain penetrant prodrug of neuroprotective D-264: Potential therapeutic application in the treatment of Parkinson's disease.
abstract: Parkinson's disease (PD) is one of the major debilitating neurodegenerative disorders affecting millions of people worldwide. Progressive loss of dopamine neurons resulting in development of motor dysfunction and other related non-motor symptoms is the hallmark of PD. Previously, we have reported on the neuroprotective property of a potent D3 preferring agonist D-264. In our goal to increase the bioavailability of D-264 in the brain, we have synthesized a modified cysteine based prodrug of D-264 and evaluated its potential in crossing the blood-brain barrier. Herein, we report the synthesis of a novel modified cysteine conjugated prodrug of potent neuroprotective D3 preferring agonist D-264 and systematic evaluation of the hydrolysis pattern of the prodrug to yield D-264 at different time intervals in rat plasma and brain homogenates using HPLC analysis. Furthermore, we have also performed in vivo experiments with the prodrug to evaluate its enhanced brain penetration ability.
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI 48202, United States.
authors.forename: Fahd
authors.initials: F
authors.lastname: Dholkawala
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI 48202, United States.
authors.forename: Chandrashekhar
authors.initials: C
authors.lastname: Voshavar
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI 48202, United States. Electronic address: adutta@wayne.edu.
authors.forename: Aloke K
authors.initials: AK
authors.lastname: Dutta
mesh_terms: D000818:Animals; D052160:Benzothiazoles; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001812:Blood-Brain Barrier; D005260:Female; D006868:Hydrolysis; D008297:Male; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy*; D010879:Piperazines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D052160:Benzothiazoles; D001713:Biphenyl Compounds; C529806:N(6)-(2-(4-(biphenyl-4-yl)piperazin-1-yl)ethyl)-N(6)-propyl-4,5,6,7-tetrahydrobenzo(d)thiazole-2,6-diamine; D018696:Neuroprotective Agents; D010879:Piperazines; D011355:Prodrugs; D013844:Thiazoles
keywords: Blood–brain barrier; D-264; Modified cysteine; Multifunctional dopamine agonist; Parkinson’s disease; Prodrug