title: Straightforward and effective synthesis of γ-aminobutyric acid transporter subtype 2-selective acyl-substituted azaspiro[4.5]decanes.
abstract: Supply of major metabolites such as γ-aminobutyric acid (GABA), β-alanine and taurine is an essential instrument that shapes signalling, proper cell functioning and survival in the brain and peripheral organs. This background motivates the synthesis of novel classes of compounds regulating their selective transport through various fluid-organ barriers via the low-affinity γ-aminobutyric acid (GABA) transporter subtype 2 (GAT2). Natural and synthetic spirocyclic compounds or therapeutics with a range of structures and biological activity are increasingly recognised in this regard. Based on pre-validated GABA transport activity, straightforward and efficient synthesis method was developed to provide an azaspiro[4.5]decane scaffold, holding a variety of charge, substituent and 3D constrain of spirocyclic amine. Investigation of the azaspiro[4.5]decane scaffold in cell lines expressing the four GABA transporter subtypes led to the discovery of a subclass of a GAT2-selective compounds with acyl-substituted azaspiro[4.5]decane core.
authors.affiliation: Organic and Medicinal Chemistry Laboratories, Université catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Ma
authors.affiliation: Organic and Medicinal Chemistry Laboratories, Université catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium.
authors.forename: Hodney
authors.initials: H
authors.lastname: Lubin
authors.affiliation: Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary.
authors.forename: Enikő
authors.initials: E
authors.lastname: Ioja
authors.affiliation: Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Kékesi
authors.affiliation: Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Simon
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Enzimology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary.
authors.forename: Ágota
authors.initials: Á
authors.lastname: Apáti
authors.affiliation: Biomembrane Research Group, Institute of Enzimology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary.
authors.forename: Tamás I
authors.initials: TI
authors.lastname: Orbán
authors.affiliation: Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Héja
authors.affiliation: Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary. Electronic address: kardos.julianna@ttk.mta.hu.
authors.forename: Julianna
authors.initials: J
authors.lastname: Kardos
authors.affiliation: Organic and Medicinal Chemistry Laboratories, Université catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium. Electronic address: istvan.marko@uclouvain.be.
authors.forename: István E
authors.initials: IE
authors.lastname: Markó
mesh_terms: D000215:Acylation; D000473:Alkanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D006801:Humans; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000473:Alkanes; D001372:Aza Compounds; D050485:GABA Plasma Membrane Transport Proteins; D013141:Spiro Compounds; D005680:gamma-Aminobutyric Acid; C012867:decane
keywords: Azaspiro[4.5]decane scaffold; GABA transporter subtype GAT2 (slc6a13); γ-Aminobutyric acid (GABA); ω-Amino acid selectivity