GABA(B) 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 antagon ize GABA(B) receptor-mediated function in a stereoselective manner. Fu rthermore, we have identified energy-minimized superimposable conforma tions of (R)-4-OH- and (S)-8-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 mechani sms in rat brain synaptic membranes, (2R,4R)-2-Me-4-OH-DAVA was shown to inhibit stereoselectively the binding of [H-3]GABA to rat brain GAB A(B) receptor sites (IC50 = 14 +/- 4 mu M). (2R, 4R)-2-Me-4-OH-DAVA (K -i = 36 mu M) and, with much lower potency, (2S,4R)-2-Me-4-OH-DAVA (K- i = 370 mu M) stereoselectively antagonized GABAB receptor-mediated fu nction 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 w as compared with the proposed receptor-active conformations of (R)-4-O H-DAVA and (S)-2-OH-DAVA. (C) 1995 Wiley-Liss, Inc.