title: Synthesis and biological evaluation of pro-drugs of GW196771, a potent glycine antagonist acting at the NMDA receptor.
abstract: GW196771 is a potent antagonist of the modulatory glycine site of the N-methyl-D-aspartate (NMDA) receptor exhibiting outstanding in vivo profile in different animal models of chronic pain. With the aim to maximize the drug delivery to the target organs a suitable "pro-drug approach" was attempted; in this regards two conjugates of GW196771 with nutrients actively transported into the brain, namely adenosine and glucose, were prepared and investigated. These compounds, were evaluated in vitro in terms of their stability in rat plasma and in vivo on rats. Although an improvement was observed in terms of brain penetration of the esters vs. the parent compound, the amount of the latter did not increase significantly, probably due to some degradation events in the brain, different from the expected ester hydrolysis, resulting in a reduced availability of GW196771.
authors.affiliation: Department of Pharmaceutical Sciences, Ferrara University, via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Angusti
authors.forename: Elisa
authors.initials: E
authors.lastname: Durini
authors.forename: Silvia
authors.initials: S
authors.lastname: Vertuani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dalpiaz
authors.forename: A
authors.initials: A
authors.lastname: Ruffo
authors.forename: Romano
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pentassuglia
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vitulli
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Barnaby
authors.forename: Stefano
authors.initials: S
authors.lastname: Manfredini
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005998:Glycine / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000627:therapeutic use; D007192:Indenes / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D009005:Monosaccharides / Q000737:chemistry / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000627:therapeutic use
chemical_list: C506656:GW 700906; C506655:GW 710922; C506654:GW196771; D007192:Indenes; D009005:Monosaccharides; D011355:Prodrugs; D011759:Pyrrolidines; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine