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Comparative Stereostructure‐Activity Studies on GABA A and GABA B Receptor Sites and GABA Uptake Using Rat Brain Membrane Preparations
Author(s) -
Falch Erik,
Hedegaard Anette,
Nielsen Lone,
Jensen Birger R.,
Hjeds Hans,
KrogsgaardLarsen Povl
Publication year - 1986
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1986.tb00695.x
Subject(s) - muscimol , gabab receptor , gabaa receptor , baclofen , aminobutyric acid , gaba receptor , chemistry , stereochemistry , synaptic membrane , receptor , gamma aminobutyric acid , agonist , biochemistry
The affinities of a number of analogues of γ‐aminobutyric acid (GABA) for GABA A and GABA B receptor sites and GABA uptake were studied using rat brain membrane preparations. Studies on the ( S )‐(+)‐and ( R )‐(‐)‐isomers of baclofen, 3‐hydroxy‐4‐aminobutyric acid (3‐OH‐GABA), and 4,5‐dihydromuscimol (DHM) revealed different stereoselectivities of these synaptic mechanisms in vitro. Although ( S )‐3‐OH‐GABA and, in particular, ( S )‐DHM were more potent than the corresponding ( R )‐isomers as inhibitors of GABA A binding, the opposite stereoselectivity was demonstrated for the GABA B binding sites. Thus, ( R )‐3‐OH‐GABA and ( R )‐baclofen were more potent than the ( S )‐isomers as inhibitors of GABA B binding, ( R )‐baclofen being some five times more potent than ( R )‐3‐OH‐GABA. These two ( R )‐isomers actually have opposite orientation of the substituents on the GABA backbones, suggesting that the lipophilic substituent of ( R )‐baclofen interacts with a structural element of the GABA B receptor site different from that that binds the very polar hydroxy group of ( R )‐3‐OH‐GABA. The O ‐methylated analogue of 3‐OH‐GABA, 3‐methoxy‐4‐aminobutyric acid (3‐OCH 3 ‐GABA), did not interact significantly with GABA B sites. The homoiogues of GABA, trans ‐4‐aminocrotonic acid ( trans‐ ACA). muscimol, and 3‐OH‐GABA, that is, 5‐aminovaleric acid (DAVA), trans ‐5‐aminopent‐2‐enoic acid, homomuscimol, and 3‐hydroxy‐5‐aminovaleric acid (3‐OH‐DAVA), respectively, were generally much weaker than the parent compounds, whereas 2‐hydroxy‐5‐aminovaleric acid (2‐OH‐DAVA) showed a significantly higher affinity for GABA B sites than the corresponding GABA analogue, 2‐hydroxy‐4‐aminobutyric acid (2‐OH‐GABA). The cyclized analogues of these amino acids, perhydrooxazine‐6‐carboxylic acid and isoxazolidine‐5‐carboxylic acid, respectively, were inactive.