Guanidino Acids Act as q1 GABA C Receptor Antagonists

Abstract GABA C receptors play a role in myopia, memory-related disorders and circadian rhythms signifying a need to develop potent and selective agents for this class of receptors. Guanidino analogs related to glycine, b-alanine and taurine were evaluated at human q 1 GABA C receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methods. Of the 12 analogs tested, 8 analogs were active as antagonists and the remaining were inactive. (S)-2-Guanidinopropionic acid (IC 50 = 2.2 lM) and guanidinoacetic acid (IC 50 = 5.4 lM; K B = 7.75 lM [pK B = 5.11 ± 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the b-alanine and GABA guanidino analogs showed reduced activity, indicating the distance between the carboxyl carbon and terminal nitrogen of the guanidino group is critical for activity. Substituting the C2-position of guanidinoacetic acid with various alkyl groups reduced activity indicating that steric effects may impact on activity. The results of this study contribute to the structure-activity-relationship profile required in developing novel therapeutic agents