Hydroxylated analogues of 5-aminovaleric acid as 4-aminobutyric acidB receptor antagonists: stereostructure-activity relationships
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Hydroxylated analogues of 5-aminovaleric acid as 4-aminobutyric acidB receptor antagonists : stereostructure-activity relationships. / Kristiansen, U; Hedegaard, A; Herdeis, C; Lund, Trine Meldgaard; Nielsen, Birgitte; Hansen, J J; Falch, E; Hjeds, H; Krogsgaard-Larsen, P.
In: Journal of Neurochemistry, Vol. 58, No. 3, 03.1992, p. 1150-9.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Hydroxylated analogues of 5-aminovaleric acid as 4-aminobutyric acidB receptor antagonists
T2 - stereostructure-activity relationships
AU - Kristiansen, U
AU - Hedegaard, A
AU - Herdeis, C
AU - Lund, Trine Meldgaard
AU - Nielsen, Birgitte
AU - Hansen, J J
AU - Falch, E
AU - Hjeds, H
AU - Krogsgaard-Larsen, P
PY - 1992/3
Y1 - 1992/3
N2 - 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.
AB - 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.
KW - Amino Acids
KW - Amino Acids, Neutral
KW - Animals
KW - GABA-A Receptor Antagonists
KW - Guinea Pigs
KW - Hydroxylation
KW - Ileum
KW - Male
KW - Stereoisomerism
KW - Structure-Activity Relationship
KW - Synaptosomes
M3 - Journal article
C2 - 1310720
VL - 58
SP - 1150
EP - 1159
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 3
ER -
ID: 49895229