Journal Article

Guanidino Acids Act as rho 1 GABA sub(C) Receptor Antagonists

Wong, Kit Yee, Duke, Rujee K, Johnston, Graham AR, Chebib, Mary, Park, Anna, Mewett, Kenneth N, Allan, Robin D, Hanrahan, Jane R, Premoli, Isabella, Gavande, Navnath

2009

Overview

GABA sub(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, beta -alanine and taurine were evaluated at human rho sub(1)GABA sub(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 sub(50)=2.2 mu M) and guanidinoacetic acid (IC sub(50)=5.4 mu M; K sub(B)=7.75 mu M [pK sub(B)=5.11 plus or minus 0; 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the beta -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.