title: New Insight into the Structure-Activity Relationships of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors UCPH-101 and UCPH-102.
abstract: In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 different substituents (R(1) ) at the 7-position in combination with eight different substituents (R(2) ) at the 4-position. Among the 63 new analogues synthesized, we identified a number of compounds that unexpectedly displayed inhibitory activities at EAAT1 in light of understanding the structure-activity relationship (SAR) of this inhibitor class extracted from previous studies. Moreover, the nature of the R(1) and R(2) substituents were observed to contribute to the functional properties of the various analogues in additive and non-additive ways. Finally, separation of the four stereoisomers of analogue 14 g (2-amino-4-([1,1'-biphenyl]-4-yl)-3-cyano-7-isopropyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene) was carried out, and in agreement with a study of a related scaffold, the R configuration at C4 was found to be mandatory for inhibitory activity, while both the C7 diastereomers were found to be active as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g-A-D showed that epimerization takes places at C7 via a ring-opening, C-C bond rotation, ring-closing mechanism.
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: 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: 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: 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: 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: 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: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Hansen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Storgaard
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: D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D013237:Stereoisomerism; 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: chromenes; excitatory amino acid transporters; glutamate; structure-activity relationships; three-component reactions