2. Academic Validation
  3. Straightforward and effective synthesis of γ-aminobutyric acid transporter subtype 2-selective acyl-substituted azaspiro[4.5]decanes

Straightforward and effective synthesis of γ-aminobutyric acid transporter subtype 2-selective acyl-substituted azaspiro[4.5]decanes

  • Bioorg Med Chem Lett. 2016 Jan 15;26(2):417-423. doi: 10.1016/j.bmcl.2015.11.100.
Xiaofeng Ma 1,  Hodney Lubin 1,  Enikő Ioja 2,  Orsolya Kékesi 2,  Ágnes Simon 2,  Ágota Apáti 3,  Tamás I Orbán 4,  László Héja 2,  Julianna Kardos 5,  István E Markó 6
Affiliations

Affiliations

  • 1 Organic and Medicinal Chemistry Laboratories, Université catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium.
  • 2 Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary.
  • 3 Laboratory of Molecular Cell Biology, Institute of Enzimology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary.
  • 4 Biomembrane Research Group, Institute of Enzimology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary.
  • 5 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.
  • 6 Organic and Medicinal Chemistry Laboratories, Université catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium. Electronic address: istvan.marko@uclouvain.be.
PMID: 26706177 DOI: 10.1016/j.bmcl.2015.11.100
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.

Keywords

Azaspiro[4.5]decane scaffold; GABA transporter subtype GAT2 (slc6a13); γ-Aminobutyric acid (GABA); ω-Amino acid selectivity.

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