GABAB antagonists: Enantiopharmacology of 5-amino-4-hydroxy-2-methylvaleric acid and X-ray structure of the eutomer

We have previously shown that (R)-5-amino-4-hydroxyvaleric acid [(R)-4-OH-DAVA] and (S)-2-OH-DAVA bind to GABA_B receptor sites and antagonize GABA_B receptor-mediated function in a stereoselective manner. Furthermore, we have identified energy-minimized superimposable conformations of (R)-4-OH- and (S)-2-OH-DAVA which are assumed to reflect the receptor-active conformations of these compounds. This paper describes the in vitro enantiopharmacology of 5-amino-4-hydroxy-2-methylvaleric acid (2-Me-4-OH-DAVA). Whereas none of the four stereoisomers showed significant affinity for GABA_A receptor sites or GABA uptake mechanisms in rat brain synaptic membranes, (2R,4R)-2-Me-4-OH-DAVA was shown to inhibit stereoselectively the binding of [³H]GABA to rat brain GABA_B receptor sites (IC₅₀ = 14 ± 4 μM). (2R,4R)-2-Me-4-OH-DAVA (K_i = 36 μM) and, with much lower potency, (2S,4R)-2-Me-4-OH-DAVA (K_i = 370 μM) stereoselectively antagonized GABA_B receptor-mediated function in the isolated guinea pig ileum. The structure of the eutomer, (2R,4R)-2-Me-4-OH-DAVA, was established by an X-ray crystallographic analysis, and the solid-state conformation of (2R,4R)-2-Me-4-OH-DAVA was compared with the proposed receptor-active conformations of (R)-4-OH-DAVA and (S)-2-OH-DAVA. © 1995 Wiley-Liss, Inc.