title: 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.
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.
authors.affiliation: Synaptic Pharmaceutical Corporation, Paramus, New Jersey 07652.
authors.forename: T G
authors.initials: TG
authors.lastname: Dhar
authors.forename: L A
authors.initials: LA
authors.lastname: Borden
authors.forename: S
authors.initials: S
authors.lastname: Tyagarajan
authors.forename: K E
authors.initials: KE
authors.lastname: Smith
authors.forename: T A
authors.initials: TA
authors.lastname: Branchek
authors.forename: R L
authors.initials: RL
authors.lastname: Weinshank
authors.forename: C
authors.initials: C
authors.lastname: Gluchowski
mesh_terms: D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D001812:Blood-Brain Barrier; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D015195:Drug Design; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins; D009557:Nipecotic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D027361:Organic Anion Transporters; D011392:Proline / Q000031:analogs & derivatives*; D051381:Rats; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D008024:Ligands; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009557:Nipecotic Acids; D027361:Organic Anion Transporters; C493413:SLC6A1 protein, human; C493416:SLC6A11 protein, human; C493418:SLC6A13 protein, human; C493415:Slc6a1 protein, rat; C030278:nipecotic acid; D005680:gamma-Aminobutyric Acid; D011392:Proline; C010983:homoproline