Glycine antagonists. Synthesis, structure, and biological effects of some bicyclic 5-isoxazolol zwitterions

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 approximately 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 nor 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.