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Azetidine derivatives as novel gamma-aminobutyric acid uptake inhibitors: synthesis, biological evaluation, and structure-activity relationship. 2010

Mark R Faust, and Georg Höfner, and Jörg Pabel, and Klaus T Wanner
Department Pharmazie, Zentrum für Pharmaforschung, LMU München, Butenandtstr. 5-13, D-81377 München, Germany.

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).

UI MeSH Term Description Entries
D002417 Cattle Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor. Beef Cow,Bos grunniens,Bos indicus,Bos indicus Cattle,Bos taurus,Cow,Cow, Domestic,Dairy Cow,Holstein Cow,Indicine Cattle,Taurine Cattle,Taurus Cattle,Yak,Zebu,Beef Cows,Bos indicus Cattles,Cattle, Bos indicus,Cattle, Indicine,Cattle, Taurine,Cattle, Taurus,Cattles, Bos indicus,Cattles, Indicine,Cattles, Taurine,Cattles, Taurus,Cow, Beef,Cow, Dairy,Cow, Holstein,Cows,Dairy Cows,Domestic Cow,Domestic Cows,Indicine Cattles,Taurine Cattles,Taurus Cattles,Yaks,Zebus
D005680 gamma-Aminobutyric Acid The most common inhibitory neurotransmitter in the central nervous system. 4-Aminobutyric Acid,GABA,4-Aminobutanoic Acid,Aminalon,Aminalone,Gammalon,Lithium GABA,gamma-Aminobutyric Acid, Calcium Salt (2:1),gamma-Aminobutyric Acid, Hydrochloride,gamma-Aminobutyric Acid, Monolithium Salt,gamma-Aminobutyric Acid, Monosodium Salt,gamma-Aminobutyric Acid, Zinc Salt (2:1),4 Aminobutanoic Acid,4 Aminobutyric Acid,Acid, Hydrochloride gamma-Aminobutyric,GABA, Lithium,Hydrochloride gamma-Aminobutyric Acid,gamma Aminobutyric Acid,gamma Aminobutyric Acid, Hydrochloride,gamma Aminobutyric Acid, Monolithium Salt,gamma Aminobutyric Acid, Monosodium Salt
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001384 Azetidines
D001692 Biological Transport The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments. Transport, Biological,Biologic Transport,Transport, Biologic
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D050485 GABA Plasma Membrane Transport Proteins A family of plasma membrane neurotransmitter transporter proteins that regulates extracellular levels of the inhibitory neurotransmitter GAMMA-AMINOBUTYRIC ACID. They differ from GABA RECEPTORS, which signal cellular responses to GAMMA-AMINOBUTYRIC ACID. They control GABA reuptake into PRESYNAPTIC TERMINALS in the CENTRAL NERVOUS SYSTEM through high-affinity sodium-dependent transport. GABA Transporter,Neurotransmitter Transport Proteins, GABA-Specific,Neurotransmitter Transporters, GABA-Specific,GABA Plasma Membrane Transporter Proteins,GABA Transporter 1,GABA Transporter 2,GABA Transporter 3,GABA Transporter 4,GABA Transporters,GAT-1 Transporter,GAT-2 Transporter,GAT-3 Transporter,GAT-4 Transporter,GAT1 Transporter,GAT2 Transporter,GAT3 Transporter,Gamma-Aminobutyric Acid Plasma Membrane Transport Proteins,GABA-Specific Neurotransmitter Transporters,GAT 1 Transporter,GAT 2 Transporter,GAT 3 Transporter,GAT 4 Transporter,Gamma Aminobutyric Acid Plasma Membrane Transport Proteins,Neurotransmitter Transport Proteins, GABA Specific,Neurotransmitter Transporters, GABA Specific,Transporter 2, GABA,Transporter, GABA,Transporter, GAT-2,Transporter, GAT-4,Transporter, GAT2,Transporters, GABA,Transporters, GABA-Specific Neurotransmitter
D058805 GABA Uptake Inhibitors Compounds that suppress or block the plasma membrane transport of GAMMA-AMINOBUTYRIC ACID by GABA PLASMA MEMBRANE TRANSPORT PROTEINS. GABA Reuptake Inhibitor,GABA Uptake Inhibitor,Gamma-Aminobutyric Acid Plasma Membrane Transport Inhibitor,GABA Reuptake Inhibitors,Gamma-Aminobutyric Acid Plasma Membrane Transport Inhibitors,Uptake Inhibitors, GABA,Uptake Inhibitors, Gamma-Aminobutyric Acid,Gamma Aminobutyric Acid Plasma Membrane Transport Inhibitor,Gamma Aminobutyric Acid Plasma Membrane Transport Inhibitors,Inhibitor, GABA Reuptake,Inhibitor, GABA Uptake,Inhibitors, GABA Reuptake,Inhibitors, GABA Uptake,Reuptake Inhibitor, GABA,Reuptake Inhibitors, GABA,Uptake Inhibitor, GABA,Uptake Inhibitors, Gamma Aminobutyric Acid
D020128 Inhibitory Concentration 50 The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture. IC50,Concentration 50, Inhibitory

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