Analogues of gamma-aminobutyric acid (GABA) and trans-4-aminocrotonic acid (TACA) substituted in the 2 position as GABAC receptor antagonists

British Journal of Pharmacology
M ChebibG A Johnston

Abstract

1. gamma-Aminobutyric acid (GABA) and trans-4-aminocrotonic acid (TACA) have been shown to activate GABAC receptors. In this study, a range of C2, C3, C4 and N-substituted GABA and TACA analogues were examined for activity at GABAC receptors. 2. The effects of these compounds were examined by use of electrophysiological recording from Xenopus oocytes expressing the human rho 1 subunit of GABAC receptors with the two-electrode voltage-clamp method. 3. trans-4-Amino-2-fluorobut-2-enoic acid was found to be a potent agonist (KD = 2.43 microM). In contrast, trans-4-amino-2-methylbut-2-enoic acid was found to be a moderately potent antagonist (IC50 = 31.0 microM and KB = 45.5 microM). These observations highlight the possibility that subtle structural substitutions may change an agonist into an antagonist. 4. 4-Amino-2-methylbutanoic acid (KD = 189 microM), 4-amino-2-methylenebutanoic acid (KD = 182 microM) and 4-amino-2-chlorobutanoic acid (KD = 285 microM) were weak partial agonists. The intrinsic activities of these compounds were 12.1%, 4.4% and 5.2% of the maximal response of GABA, respectively. These compounds more effectively blocked the effects of the agonist, GABA, giving rise to KB values of 53 microM and 101 microM, respe...Continue Reading

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Citations

Feb 1, 1990·The Journal of Hand Surgery : Journal of the British Society for Surgery of the Hand·P G Slattery
Nov 17, 2001·European Journal of Pharmacology·M ChebibG A Johnston
Jan 19, 2000·Trends in Pharmacological Sciences·J Bormann
Mar 25, 2011·Future Medicinal Chemistry·Clarissa K L NgMary Chebib
Nov 8, 2003·Bioorganic & Medicinal Chemistry·Dorte KrehanMary Chebib
Mar 4, 2008·Chemical Biology & Drug Design·Heba Abdel-HalimMary Chebib
Apr 24, 2009·Neurochemical Research·Mary ChebibJane R Hanrahan
Apr 26, 2000·Journal of Medicinal Chemistry·M Chebib, G A Johnston
Jul 13, 2006·The Journal of Physical Chemistry. a·Deborah L CrittendenMeredith J T Jordan

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