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

Abstract

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.