Hydroxylated analogues of 5-aminovaleric acid as 4-aminobutyric acidB receptor antagonists: stereostructure-activity relationships.
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 acidB (GABAB) agonist (R)-(-)-4-amino-3-hydroxybutyric acid [(R)-(-)-3-OH-GABA] and the GABAB antagonist 5-aminovaleric acid (DAVA). (S)-(-)-2-OH-DAVA and (R)-(-)-4-OH-DAVA showed a moderately potent affinity for GABAB receptor sites in rat brain and showed GABAB antagonist effects in a guinea pig ileum preparation. The respective enantiomers, (R)-(+)-2-OH-DAVA and (S)-(+)-4-OH-DAVA, were markedly weaker in both test systems. All four compounds were weak inhibitors of GABAA 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 conformationally flexible compounds during their interaction with GABAB receptors. The present studies emphasize the similar, but distinct, constraints imposed on agonists and antagonists for GABAB receptors.
Kristiansen
U
U
Department of Organic Chemistry, Royal Danish School of Pharmacy, Copenhagen.
Hedegaard
A
A
Herdeis
C
C
Lund
T M
TM
Nielsen
B
B
Hansen
J J
JJ
Falch
E
E
Hjeds
H
H
Krogsgaard-Larsen
P
P
D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism*; D021542:Amino Acids, Neutral; D000818:Animals; D058787:GABA-A Receptor Antagonists; D006168:Guinea Pigs; D006900:Hydroxylation; D007082:Ileum / Q000378:metabolism; D008297:Male; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
D000596:Amino Acids; D021542:Amino Acids, Neutral; D058787:GABA-A Receptor Antagonists; C004387:2-amino-5-hydroxyvaleric acid; C013809:5-aminovaleric acid