Journal
NEUROCHEMICAL RESEARCH
Volume 34, Issue 10, Pages 1704-1711Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11064-009-9968-x
Keywords
GABA(C) receptors; Guanidino acids; Taurine; Glycine; beta-Alanine
Categories
Funding
- National Health and Medical Research Council of Australia
- Department of Pharmacology
- The University of Sydney
- Endevour International Postgraduate Scholarship
- John Lamberton top-up scholarship
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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 (IC50 = 2.2 mu M) and guanidinoacetic acid (IC50 = 5.4 mu M; K (B) = 7.75 mu M [pK (B) = 5.11 +/- A 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.
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