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Guanidino Acids Act as ρ1 GABAC Receptor Antagonists

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Abstract

GABAC 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, β-alanine and taurine were evaluated at human ρ1GABAC 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 μM) and guanidinoacetic acid (IC50 = 5.4 μM; K B = 7.75 μM [pK B = 5.11 ± 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the β-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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Abbreviations

TPMPA:

(1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid

CACA:

(Z)-4-Aminobut-2-enoic acid

(+)-CAMP:

(+)-cis-2-Aminomethylcyclopropanecarboxylic acid

cis- and trans-3-ACPBPA:

cis- and trans-(3-aminocyclopentanyl)butylphosphinic acid

ZAPA:

(Z)-3-[(Aminoiminomethyl)thio]prop-2-enoic acid

(R)- and (S)-2-Me-GABA:

(R)- and (S)-4-Amino-2-methyl-butyric acid

GAA:

Guanidinoacetic acid

5-MeIAA:

5-Methyl imidazole-4-acetic acid

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Acknowledgments

We are very grateful for the National Health and Medical Research Council of Australia for financial support and the Department of Pharmacology, The University of Sydney, for managing and maintaining the Xenopus laevis colony. N.G. acknowledges support from an Endevour International Postgraduate Scholarship and the John Lamberton top-up scholarship.

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Authors and Affiliations

  1. Faculty of Pharmacy A15, The University of Sydney, Sydney, NSW, 2006, Australia

    Mary Chebib, Navnath Gavande, Kit Yee Wong, Anna Park, Isabella Premoli & Jane R. Hanrahan

  2. Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, D06, The University of Sydney, Sydney, NSW, 2006, Australia

    Kenneth N. Mewett, Robin D. Allan, Rujee K. Duke & Graham A. R. Johnston

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  1. Mary Chebib
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  2. Navnath Gavande
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Correspondence to Mary Chebib.

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Chebib, M., Gavande, N., Wong, K.Y. et al. Guanidino Acids Act as ρ1 GABAC Receptor Antagonists. Neurochem Res 34, 1704–1711 (2009). https://doi.org/10.1007/s11064-009-9968-x

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  • DOI: https://doi.org/10.1007/s11064-009-9968-x

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