1-(3-(9H-carbazol-9-yl)-1-propyl)-4-(2-methoxyphenyl)-4-piperidinol, a novel subtype selective inhibitor of the mouse type II GABA-transporter.
The selectivity of new derivatives of the gamma-aminobutyric acid (GABA)-uptake inhibitor, tiagabine was characterized at the four cloned mouse GABA transporters (mGAT1 through mGAT4) by measuring [3H]-GABA uptake into stably transfected baby hamster kidney cells. While tiagabine is a highly selective inhibitor of mGAT1 (Ki = 0.11 +/- 0.02 microM), these derivatives exhibited low potencies at mGAT1 but differential activities at mGAT2, mGAT3 and mGAT4. In particular, 1-(3-(9H-carbazol-9-yl)-1-propyl)-4-(2-methoxyphenyl)-4-piperidino l (NNC 05-2090) was a potent inhibitor of mGAT2 (Ki = 1.4 +/- 0.3 microM) showing at least 10 fold selectivity over mGAT1, mGAT3 and mGAT4. NNC 05-2090 is the first subtype selective inhibitor of mGAT2 and may represent a novel useful tool for investigating the physiological roles of GAT2 in the brain and periphery.
Thomsen
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Novo Nordisk A/S, Department of Molecular Pharmacology, Måløv, Denmark.
Sørensen
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Egebjerg
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D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D006224:Cricetinae; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D026901:Membrane Transport Proteins; D051379:Mice; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009557:Nipecotic Acids / Q000494:pharmacology; D027361:Organic Anion Transporters; D010880:Piperidines / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives*; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C107429:NNC 05-2090; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D027361:Organic Anion Transporters; D010880:Piperidines; C490439:Slc6a12 protein, mouse; C493419:Slc6a13 protein, mouse; C030278:nipecotic acid; D005680:gamma-Aminobutyric Acid; D011392:Proline; C010983:homoproline; D000078308:Tiagabine