Azetidine derivatives as novel gamma-aminobutyric acid uptake inhibitors: synthesis, biological evaluation, and structure-activity relationship.

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Citation

Faust MR, Hofner G, Pabel J, Wanner KT

Azetidine derivatives as novel gamma-aminobutyric acid uptake inhibitors: synthesis, biological evaluation, and structure-activity relationship.

Eur J Med Chem. 2010 Jun;45(6):2453-66. doi: 10.1016/j.ejmech.2010.02.029. Epub 2010 Feb 14.

PubMed ID
20219271 [ View in PubMed
]
Abstract

In this study azetidine derivatives representing conformationally constrained GABA or beta-alanine analogs were evaluated for their potency as GABA-uptake inhibitors. The study comprised derivatives substituted in 2- as well as in 3-position with either an acetic acid moiety or a carboxylic acid function. In addition, azetidine derivatives bearing a tetrazole ring as a bioisosteric substitute for a carboxylic acid group were included. 3-Hydroxy-3-(4-methoxyphenyl)azetidine derivatives were explored as analogs of the known GABA-uptake inhibitor NNC-05-2045 exhibiting an azetidine ring instead of a piperidine ring present in the latter. Both, N-unsubstituted compounds as well as their N-alkylated lipophilic derivatives, were biologically evaluated for their affinity to the GAT-1 and GAT-3 transporters. Azetidin-2-ylacetic acid derivatives provided with a 4,4-diphenylbutenyl or 4,4-bis(3-methyl-2-thienyl)butenyl moiety as lipophilic residue were found to exhibit the highest potency at GAT-1 with IC50 values of 2.83+/-0.67 microM and 2.01+/-0.77 microM, respectively. The most potent GAT-3 inhibitor among these compounds appeared to be the beta-alanine analog 1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}azetidine-3-carboxylic acid (12d) displaying an IC50 value of 15.3+/-4.5 microM. Whereas the tetrazole derivatives showed no potency as GABA-uptake inhibitors, the 3-hydroxy-3-(4-methoxyphenyl)azetidine derivatives exhibited moderate affinity to GAT-1 (compound 18b: IC50=26.6+/-3.3 microM) and to GAT-3 (compound 18e: IC50=31.0+/-4.7 microM).

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
GuvacineSodium- and chloride-dependent GABA transporter 2IC 50 (nM)66000N/AN/ADetails
GuvacineSodium- and chloride-dependent GABA transporter 3IC 50 (nM)110000N/AN/ADetails