Glycine Antagonists. Synthesis, Structure, and Biological Effects of Some Bicyclic 5-Isoxazolol Zwitterions

Article abstract of DOI:10.1021/jm00152a010

The bicyclic 5-isoxazolol zwitterions 4,5,6,7-tetrahydroisoxazolo<4,3-c>pyridin-3-ol (3, iso-THPO), 5,6,7,8-tetrahydro-4H-isoxazolo<4,3-c>azepin-3-ol (12, iso-THAO), and 5,6,7,8-tetrahydro-4H-isoxazolo<3,4-c>azepin-3-ol (13, iso-THIA), which are structurally related to the glycine antagonist 5,6,7,8-tetrahydro-4H-isoxazolo<3,4-d>azepin-3-ol (iso-THAZ), have been synthesized and tested biologically.All of these compounds were glycine antagonists approximetely equipotent with iso-THAZ during microelectrophoretic ejection near cat spinal neurons.In contrast to iso-THAZ, which also interacts with 4-aminobutyric acid (GABA) receptors in rat brains, neither 12 or 13 show any significant affinities for GABA binding or uptake mechanisms in vitro.The glycine antagonist 3 was, however, shown also to be a moderately potent inhibitor of GABA uptake.The structure of 12 was established by an X-ray analysis.The bond lengths of the 5-isoxazolol anionic moiety of 12 are in agreement with a pronounced delocalization of the negative charge of this compound.