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Hydroxylated Analogues of 5‐Aminovaleric Acid as 4‐Aminobutyric AcidB Receptor Antagonists: Stereostructure‐Activity Relationships
Author(s) -
Kristiansen Uffe,
Hedegaard Anette,
Herdeis Claus,
Lund Trine M.,
Nielsen Birgitte,
Hansen Jan J.,
Falch Erik,
Hjeds Hans,
KrogsgaardLarsen Povl
Publication year - 1992
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.1471-4159.1992.tb09374.x
Subject(s) - aminobutyric acid , chemistry , stereochemistry , receptor , biochemistry
The (R) and (S) forms of 5‐amino‐2‐hydroxyvaleric acid (2‐OH‐DAVA) and 5‐amino‐4‐hydroxyvaleric acid (4‐OH‐DAVA) were designed as structural hybrids of the 4‐aminobutyric acid B (GABA B ) agonist (R)‐(–)‐4‐amino‐3‐hydroxybutyric acid [(R)‐(–)‐3‐OH‐GABA] and the GABA B antagonist 5‐aminovaleric acid (DAVA). (S)‐(–)‐2‐OH‐DAVA and (R)‐(−)‐4‐OH‐DAVA showed a moderately potent affinity for GABA B receptor sites in rat brain and showed GABA B antagonist effects in a guinea pig ileurn preparation. The respective enantiomers, (R)‐(+)‐2‐OH‐DAVA and (S)‐ (+)‐4‐OH‐DAVA, were markedly weaker in both test systems. AH four compounds were weak inhibitors of GABA A receptor binding in rat brain, and none of them significantly affected synaptosomal GABA uptake. Based on molecular modeling studies it has been demonstrated that low‐energy conformations of (R)‐(–)‐3‐OH‐GABA, (S)(–)‐2‐OH‐DAVA, and (R)‐(–)4‐OH‐DAVA can be superimposed. These conformations may reflect the shapes adopted by these conforma‐tionally flexible compounds during their interaction with GABA B receptors. The present studies emphasize the similar, but distinct, constraints imposed on agonists and antagonists for GABA B receptors.