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Analogues of γ ‐aminobutyric acid (GABA) and trans ‐4‐aminocrotonic acid (TACA) substituted in the 2 position as GABA C receptor antagonists
Author(s) -
Chebib Mary,
Vandenberg Robert J.,
Johnston Graham A. R.
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701533
Subject(s) - agonist , partial agonist , antagonist , receptor , gabaa receptor , amino acid , chemistry , stereochemistry , aminobutyric acid , biochemistry
1 γ‐Aminobutyric acid (GABA) and trans ‐4‐aminocrotonic acid (TACA) have been shown to activate GABA C receptors. In this study, a range of C2, C3, C4 and N‐substituted GABA and TACA analogues were examined for activity at GABA C receptors. 2 The effects of these compounds were examined by use of electrophysiological recording from Xenopus oocytes expressing the human ρ 1 subunit of GABA C receptors with the two‐electrode voltage‐clamp method. 3 trans ‐4‐Amino‐2‐fluorobut‐2‐enoic acid was found to be a potent agonist ( K D =2.43 μ m ). In contrast, trans ‐4‐amino‐2‐methylbut‐2‐enoic acid was found to be a moderately potent antagonist (IC 50 =31.0 μ m and K B =45.5 μ m ). These observations highlight the possibility that subtle structural substitutions may change an agonist into an antagonist. 4 4‐Amino‐2‐methylbutanoic acid ( K D =189 μ m ), 4‐amino‐2‐methylenebutanoic acid ( K D =182 μ m ) and 4‐amino‐2‐chlorobutanoic acid ( K D =285 μ m ) 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 K B values of 53 μ m and 101 μ m , respectively. 5 The sulphinic acid analogue of GABA, homohypotaurine, was found to be a potent partial agonist ( K D =4.59 μ m , intrinsic activity 69%). 6 It was concluded that substitution of a methyl or a halo group in the C2 position of GABA or TACA is tolerated at GABA C receptors. However, there was dramatic loss of activity when these groups were substituted at the C3, C4 and nitrogen positions of GABA and TACA. 7 Molecular modelling studies on a range of active and inactive compounds indicated that the agonist/competitive antagonist binding site of the GABA C receptor may be smaller than that of the GABA A and GABA B receptors. It is suggested that only compounds that can attain relatively flat conformations may bind to the GABA C receptor agonist/competitive antagonist binding site.