Guanidino acids act as rho1 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, beta-alanine and taurine were evaluated at human rho(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 microM) and guanidinoacetic acid (IC(50) = 5.4 microM; K (B) = 7.75 microM [pK (B) = 5.11 +/- 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.

• Authors: Mary Chebib, Navnath Gavande, Kit Yee Wong, Anna Park, Isabella Premoli, Kenneth N Mewett, Robin D Allan, Rujee K Duke, Graham A R Johnston, Jane R Hanrahan
• Journal: Neurochemical research (Neurochem Res) Vol. 34 Issue 10 Pg. 1704-11 (Oct 2009) ISSN: 1573-6903 [Electronic] United States
• PMID: 19387831 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GABA Antagonists
• Guanidines
• Propionates
• Receptors, GABA
• Recombinant Proteins
• rho1 GABA(C) receptor, human
• beta-Alanine
• Taurine
• taurocyamine
• glycocyamine
• Glycine
• guanidinopropionic acid

Topics

• Animals
• Dose-Response Relationship, Drug
• Female
• GABA Antagonists (chemical synthesis, metabolism, pharmacology)
• Glycine (analogs & derivatives, chemical synthesis, metabolism, physiology)
• Guanidines (chemical synthesis, metabolism, pharmacology)
• Humans
• Oocytes (chemistry, metabolism)
• Propionates (chemical synthesis, metabolism, pharmacology)
• Receptors, GABA (biosynthesis, genetics, metabolism)
• Recombinant Proteins (antagonists & inhibitors, biosynthesis, chemistry, genetics)
• Taurine (analogs & derivatives, chemical synthesis, metabolism)
• Xenopus laevis
• beta-Alanine (metabolism)