Dataset Information

3-Aryl-3-arylmethoxyazetidines. A new class of high affinity ligands for monoamine transporters.

ABSTRACT: A series of 3-aryl-3-arylmethoxy-azetidines were synthesized and evaluated for binding affinities at dopamine and serotonin transporters. The 3-aryl-3-arylmethoxyazetidines were generally SERT selective with the dichloro substituted congener 7c (Ki=1.0 nM) and the tetrachloro substituted derivative 7i (Ki=1.3 nM) possessing low nanomolar affinity for the SERT. The 3-(3,4-dichlorophenyl-3-phenylmethoxyazetidine (7g) exhibited moderate affinity at both DAT and SERT transporters and suggests that substitution of the aryl rings can be used to tune the mononamine transporter affinity.

SUBMITTER: Thaxton A

PROVIDER: S-EPMC3733996 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

3-Aryl-3-arylmethoxyazetidines. A new class of high affinity ligands for monoamine transporters.

Thaxton Amber A Izenwasser Sari S Wade Dean D Stevens Edwin D ED Mobley David L DL Jaber Vivian V Lomenzo Stacey A SA Trudell Mark L ML

Bioorganic & medicinal chemistry letters 20130529 15

A series of 3-aryl-3-arylmethoxy-azetidines were synthesized and evaluated for binding affinities at dopamine and serotonin transporters. The 3-aryl-3-arylmethoxyazetidines were generally SERT selective with the dichloro substituted congener 7c (Ki=1.0 nM) and the tetrachloro substituted derivative 7i (Ki=1.3 nM) possessing low nanomolar affinity for the SERT. The 3-(3,4-dichlorophenyl-3-phenylmethoxyazetidine (7g) exhibited moderate affinity at both DAT and SERT transporters and suggests that s ...[more]

PMID: 23806554

Similar Datasets

Project description:The importance of the family of high affinity ammonium transporters is demonstrated by the presence of these proteins in all domains of life, including bacteria, archaea, fungi, plants, and humans. The majority of the proteins that have been studied from this family show high affinity and selectivity for ammonium, are impermeable to alkaline cations, saturate rapidly at low millimolar concentrations and most of them, are also permeable to methylammonium. Crystallization of homologue proteins from bacteria and archaea has demonstrated that the functional entity corresponds to a trimer, with each monomer maintaining a conductive pore. Through molecular modeling, it has been demonstrated that even though the identity of the proteins between bacteria/archaea with those from plants is below 25%, the latter seem to maintain similar tertiary and quaternary structures, an observation that has helped to address the functionality of conserved residues by means of mutational analysis. Results have shown that changes in the extracellular binding site of some plant transporters may result in their inhibition or reduction in transport activity, while in Escherichia coli, dissimilar replacements like Phe/Ala or Ser/Leu that eliminate possible ?-interactions or H-bonds with ammonium, respectively, lead to more active transporters. Active mutants with changes in the pair of conserved His in the center of the transporter suggest these residues are dispensable. Additional mutations have identified other important amino acids, both in the entrance of the pore and in cytoplasmic loops. Regulation of this family of transporters can be achieved by interactions of the C-terminal with cytoplasmic loops within the same monomer, or with a neighbor in the trimer. Depending on the interacting residues, these contacts may lead to the activation or inhibition of the protein. The aim of this review is to critically evaluate the newest findings on the role of the proposed amino acids that structure the ammonium pathway, as well as highlight the importance of additional residues that have been identified through mutational analyses.

Dataset Information

3-Aryl-3-arylmethoxyazetidines. A new class of high affinity ligands for monoamine transporters.

Publications

3-Aryl-3-arylmethoxyazetidines. A new class of high affinity ligands for monoamine transporters.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets