Synthesis and biological evaluation of aminomethylphenol derivatives as inhibitors of the murine GABA transporters mGAT1-mGAT4

A series of N-substituted aminomethylphenol derivatives was synthesized by reductive amination. To study the inhibitory potency of the target compounds at the murine GABA transporters (mGAT1-mGAT4), a [H-3]GABA uptake test system in a 96-well format based on HEK cells stably expressing mGAT1-mGAT4 was established and validated. Inhibitory potencies at mGAT1-mGAT4 in the micromolar range and a slight subtype selectivity for mGAT3 were observed for the synthesized aminomethylphenol derivatives. Among the compounds investigated 5-n-dodecylaminomethyl-2-methoxyphenol (21) was found to be most potent with an IC50 value at mGAT3 of about 3 mu M. (C) 2008 Elsevier Masson SAS. All rights reserved.