TY - JOUR
T1 - Straightforward and effective synthesis of γ-aminobutyric acid transporter subtype 2-selective acyl-substituted azaspiro[4.5]decanes
AU - Ma, Xiaofeng
AU - Lubin, Hodney
AU - Ioja, Eniko
AU - Kékesi, Orsolya
AU - Simon, Ágnes
AU - Apáti, Ágota
AU - Orbán, Tamás I.
AU - Héja, László
AU - Kardos, Julianna
AU - Markó, István E.
PY - 2016/1/15
Y1 - 2016/1/15
N2 - 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.
AB - 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.
KW - Azaspiro[4.5]decane scaffold
KW - GABA transporter subtype GAT2 (slc6a13)
KW - γ-Aminobutyric acid (GABA)
KW - ω-Amino acid selectivity
UR - http://www.scopus.com/inward/record.url?scp=84952935630&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2015.11.100
DO - 10.1016/j.bmcl.2015.11.100
M3 - Article
C2 - 26706177
AN - SCOPUS:84952935630
SN - 0960-894X
VL - 26
SP - 417
EP - 423
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 2
ER -