Premium
STRUCTURE‐ACTIVITY STUDIES ON THE INHIBITION OF GABA BINDING TO RAT BRAIN MEMBRANES BY MUSCIMOL AND RELATED COMPOUNDS
Author(s) -
KrogsgaardLarsen P.,
Johnston G. A. R.
Publication year - 1978
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1978.tb10469.x
Subject(s) - muscimol , nipecotic acid , gabaa receptor , chemistry , gaba receptor , stereochemistry , biochemistry , receptor , pharmacology , biology , neurotransmitter
— A series of compounds structurally related to muscimol (5‐aminomethyl‐3‐isoxazolol) was tested as inhibitors of the sodium‐independent binding of GABA to membranes from rat brain. Muscimol, 5‐(l‐aminoethyl)‐3‐isoxazolol, 5‐(2‐aminoethyl)‐3‐isoxazolol (homomuscimol), and the bicyclic derivative 4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol (THIP) were relatively potent inhibitors of GABA binding. THIP is an analogue of muscimol locked in a folded conformation. The structurally related compound 1,2,3,6‐tetrahydropyridine‐4‐carboxylic acid (isoguvacine), a semirigid analogue of trans‐4‐aminocrotonic acid, was also a potent inhibitor of GABA binding. Apart from muscimol, these inhibitors of GABA binding did not influence the sodium‐dependent,‘high‐affinity’ uptake of GABA in rat brain slices, whereas the potent GABA uptake inhibitors guvacine and nipecotic acid did not influence GABA binding. The present results support previous findings that different conformational modes of GABA interact with GABA postsynaptic receptors and the neuronal GABA transport system in rat brain, and indicate that the ‘active conformation’ of GABA with respect to the receptors is partially folded and almost planar. Based on a comparison of the present results with previous in vivo studies the structural requirements for GABA‐like activity in rat cerebral cortex and cat spinal cord seem to be somewhat different.