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.

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azetidines / chemical synthesis
  • Azetidines / chemistry*
  • Azetidines / pharmacology*
  • Biological Transport / drug effects
  • Cattle
  • GABA Plasma Membrane Transport Proteins / metabolism
  • GABA Uptake Inhibitors
  • Inhibitory Concentration 50
  • Structure-Activity Relationship
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Azetidines
  • GABA Plasma Membrane Transport Proteins
  • GABA Uptake Inhibitors
  • azetidine
  • gamma-Aminobutyric Acid