HYDROXYLATED ANALOGS 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 structral 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 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 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 conformationally 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.