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.
D000818:Animals; D005998:Glycine / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010080:Oxazoles / Q000138:chemical synthesis*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D007555:Isoxazoles; D010080:Oxazoles; D011963:Receptors, GABA-A; D005998:Glycine