title: Azetidine derivatives as novel gamma-aminobutyric acid uptake inhibitors: synthesis, biological evaluation, and structure-activity relationship.
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).
authors.affiliation: Department Pharmazie, Zentrum für Pharmaforschung, LMU München, Butenandtstr. 5-13, D-81377 München, Germany.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Faust
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.forename: Jörg
authors.initials: J
authors.lastname: Pabel
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002417:Cattle; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D058805:GABA Uptake Inhibitors; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D001384:Azetidines; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; C082735:azetidine; D005680:gamma-Aminobutyric Acid