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 (GAB A)-uptake inhibitor, tiagabine was characterized at the four cloned mo use GABA transporters (mGAT1 through mGAT4) by measuring [H-3]-GABA up take into stably transfected baby hamster kidney cells. While tiagabin e is a highly selective inhibitor of mGAT1 (K-i=0.11+/-0.02 mu M), the se derivatives exhibited low potencies at mGAT1 but differential activ ities at mGAT2, mGAT3 and mGAT4. In particular, -9-yl)-1-propyl)-4-(2- methoxyphenyl)-4-piperidinol (MNC 05-2090) was a potent inhibitor of m GAT2 (K-i = 1.4+/-0.3 mu M) showing at least 10 fold selectivity over mGAT1, mGAT3 and mGAT4. NNC 05-2090 is the first subtype selective inh ibitor of mGAT2 and may represent a novel useful tool for investigatin g the physiological roles of GAT2 in the brain and periphery.