title: Design, Synthesis and Biological Evaluation of Brain-Targeted Thiamine Disulfide Prodrugs of Ampakine Compound LCX001.
abstract: Ampakine compounds have been shown to reverse opiate-induced respiratory depression by activation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. However, their pharmacological exploitations are hindered by low blood-brain barrier (BBB) permeability and limited brain distribution. Here, we explored whether thiamine disulfide prodrugs with the ability of "lock-in" can be used to solve these problems. A series of thiamine disulfide prodrugs 7a-7f of ampakine compound LCX001 was synthesized and evaluated. The trials in vitro showed that prodrugs 7e, 7d, 7f possessed a certain stability in plasma and quickly decomposed in brain homogenate by the disulfide reductase. In vivo, prodrug 7e decreased the peripheral distribution of LCX001 and significantly increased brain distribution of LCX001 after i.v. administration. This compound showed 2.23- and 3.29-fold greater increases in the AUC0-t and MRT0-t of LCX001 in brain, respectively, than did LCX001 itself. A preliminary pharmacodynamic study indicated that the required molar dose of prodrug 7e was only one eighth that of LCX001 required to achieve the same effect in mice. These findings provide an important reference to evaluate the clinical outlook of ampakine compounds.
authors.affiliation: Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. be_xiaodian@163.com.
authors.forename: Dian
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. mengfh331@126.com.
authors.forename: Fan-Hua
authors.initials: FH
authors.lastname: Meng
authors.affiliation: Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. twotou3@126.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.affiliation: Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. yongzhabc@126.com.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yong
authors.affiliation: Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. fri_autumn@163.com.
authors.forename: Jin-Qiu
authors.initials: JQ
authors.lastname: Liu
authors.affiliation: Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. hapwave@163.com.
authors.forename: Xin-Bo
authors.initials: XB
authors.lastname: Zhou
authors.affiliation: Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. lis@bmi.ac.cn.
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003863:Depression / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D053610:Opiate Alkaloids / Q000633:toxicity; D010069:Oxadiazoles / Q000008:administration & dosage*; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis; D018091:Receptors, AMPA / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D013831:Thiamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D014018:Tissue Distribution
chemical_list: D053610:Opiate Alkaloids; D010069:Oxadiazoles; D011355:Prodrugs; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D013831:Thiamine; C000613070:LCX001; C013293:thiamine disulfide
keywords: ampakines; brain distribution; opiate; respiratory depression; thiamine disulfide prodrugs