title: Bioavailability Studies and in vitro Profiling of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor UCPH-102.
abstract: Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH-101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood-brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.) administration (40 mg kg(-1) ) of the closely related analogue UCPH-102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 μm after 1 h. Three analogue series were designed and synthesized to improve the bioavailability profile of UCPH-102, but none displayed substantially improved properties in this respect. In vitro profiling of UCPH-102 (10 μm) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is completely selective for EAAT1. Finally, in a rodent locomotor model, p.o. administration of UCPH-102 (20 mg kg(-1) ) did not induce acute effects or any visible changes in behavior.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
authors.forename: Isabell
authors.initials: I
authors.lastname: Haym
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
authors.forename: Tri H V
authors.initials: TH
authors.lastname: Huynh
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
authors.forename: Stinne W
authors.initials: SW
authors.lastname: Hansen
authors.affiliation: Technical University of Denmark, Center for Nuclear Technologies, DTU Nutech/Hevesy Laboratory, Frederiksborgvej 399, Building 202, 4000, Roskilde, Denmark.
authors.forename: Martin H F
authors.initials: MH
authors.lastname: Pedersen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
authors.forename: Josep A
authors.initials: JA
authors.lastname: Ruiz
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
authors.forename: Mette N
authors.initials: MN
authors.lastname: Erichsen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Gynther
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
authors.forename: Walden E
authors.initials: WE
authors.lastname: Bjørn-Yoshimoto
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
authors.forename: Bjarke
authors.initials: B
authors.lastname: Abrahamsen
authors.affiliation: H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
authors.forename: Jesper F
authors.initials: JF
authors.lastname: Bastlund
authors.affiliation: H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
authors.forename: Anette L
authors.initials: AL
authors.lastname: Eriksen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark. lebu@sund.ku.dk.
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C553295:2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile; D001578:Benzopyrans; D027341:Excitatory Amino Acid Transporter 1
keywords: EAAT1; blood-brain barrier; in vitro profiling; in vivo administration; inhibitors; structure-activity relationships