2. Academic Validation
  3. Bioavailability Studies and in vitro Profiling of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor UCPH-102

Bioavailability Studies and in vitro Profiling of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor UCPH-102

  • ChemMedChem. 2016 Feb 17;11(4):403-19. doi: 10.1002/cmdc.201500527.
Isabell Haym 1,  Tri H V Huynh 1,  Stinne W Hansen 1,  Martin H F Pedersen 2,  Josep A Ruiz 1,  Mette N Erichsen 1,  Mikko Gynther 3,  Walden E Bjørn-Yoshimoto 1,  Bjarke Abrahamsen 1,  Jesper F Bastlund 4,  Christoffer Bundgaard 4,  Anette L Eriksen 1,  Anders A Jensen 1,  Lennart Bunch 5
Affiliations

Affiliations

  • 1 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
  • 2 Technical University of Denmark, Center for Nuclear Technologies, DTU Nutech/Hevesy Laboratory, Frederiksborgvej 399, Building 202, 4000, Roskilde, Denmark.
  • 3 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland.
  • 4 H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark.
  • 5 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark. [email protected].
PMID: 26797816 DOI: 10.1002/cmdc.201500527
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.

Keywords

EAAT1; blood-brain barrier; in vitro profiling; in vivo administration; inhibitors; structure-activity relationships.

Figures
Products