Design, synthesis and evaluation of substituted triarylnipecotic acid derivatives as GABA uptake inhibitors: identification of a ligand with moderate affinity and selectivity for the cloned human GABA transporter GAT-3

J Med Chem. 1994 Jul 22;37(15):2334-42. doi: 10.1021/jm00041a012.

Abstract

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system. Molecular biology has revealed the presence of four high-affinity GABA transporters in the brain, GAT-1, GAT-2, GAT-3, and BGT-1, the latter transporting both GABA and the osmolyte Betaine. We have shown that known GABA uptake inhibitors such as SK&F 89976-A, CI-966, and Tiagabine exhibit high affinity and selectivity for GAT-1. In the present paper we describe the design and synthesis of a novel series of triarylnipecotic acid derivatives for evaluation as GABA uptake inhibitors. The design lead for this series of compounds was the nonselective GABA uptake inhibitor EGYT-3886, [(-)-2-phenyl-2-[(dimethylamino)ethoxy]-(1R)- 1,7,7-trimethylbicyclo[2.2.1]heptane]. From this series of compounds (S)-1-[2-[tris(4-methoxyphenyl)methoxy]ethyl]-3-piperidinecarboxylic+ ++ (S)-1-[2-[tris(4-methoxyphenyl)methoxy]ethyl]-3-piperidinecarboxylic+ ++ acid, 4(S) was identified as a novel ligand with selectivity for GAT-3. 4(S) displayed an IC50 of 5 microM at GAT-3, 21 microM at GAT-2, > 200 microM at GAT-1, and 140 microM at BGT-1. This compound will be an important tool for evaluating the role of GAT-3 in neural function.

MeSH terms

  • Animals
  • Binding Sites
  • Biological Transport
  • Blood-Brain Barrier
  • Carrier Proteins / drug effects*
  • Carrier Proteins / metabolism
  • Cell Line
  • Cloning, Molecular
  • Drug Design
  • GABA Antagonists
  • GABA Plasma Membrane Transport Proteins
  • Humans
  • Ligands
  • Membrane Proteins / drug effects*
  • Membrane Proteins / metabolism
  • Membrane Transport Proteins*
  • Nipecotic Acids / chemistry
  • Nipecotic Acids / pharmacokinetics
  • Nipecotic Acids / pharmacology*
  • Organic Anion Transporters*
  • Proline* / analogs & derivatives*
  • Rats
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Carrier Proteins
  • GABA Antagonists
  • GABA Plasma Membrane Transport Proteins
  • Ligands
  • Membrane Proteins
  • Membrane Transport Proteins
  • Nipecotic Acids
  • Organic Anion Transporters
  • SLC6A1 protein, human
  • SLC6A11 protein, human
  • SLC6A13 protein, human
  • Slc6a1 protein, rat
  • nipecotic acid
  • gamma-Aminobutyric Acid
  • Proline
  • homoproline