A series of heterocyclic GABA analogues related to muscimol (5‐aminomethyl‐3‐isoxazolol) were tested as depressants of the firing of GABA sensitive neurones on the cat spinal cord, and as inhibitors of the sodium‐independent binding of GABA to rat brain membranes. Furthermore, the compounds were examined as inhibitors of GABA uptake into rat brain slices and as inhibitors of the activities of the GABA‐metabolizing enzymes L‐glutamate 1‐carboxylyase and GABA:2‐oxoglutarate aminotransferase.Dihydromuscimol [(RS)‐4,5‐dihydromuscimol] and thiomuscimol (5‐aminomethyl‐3‐isothiazolol) were approximately equipotent to muscimol as bicuculline‐sensitive depressants of neuronal firing and as inhibitors of GABA binding. The structurally related compounds isomuscimol (3‐aminomethyl‐5‐isoxa‐zolol) and azamuscimol (5‐aminomethyl‐3‐pyrazolol) were much weaker than muscimol as GABA agonists. The affinity of the compounds for GABA receptor sites in vitro is in agreement with their relative potency as GABA receptor agonists in vivo. The rat brain synaptic membranes used for the GABA receptor binding studies were prepared by two procedures, which were shown to have a pronounced influence on the observed potency of the inhibitors of GABA binding.The compounds were weak or inactive as inhibitors of the uptake of GABA into rat brain slices and of the activity of GABA: 2‐oxoglutarate aminotransferase in vitro. Azamuscimol and 2‐methylaza‐muscimol were moderately potent inhibitors.of the activity of L‐glutamate 1‐carboxylyase in vitro. This inhibition by azamuscimol was timedependent following pseudo‐first‐order kinetics, consistent with azamuscimol acting as a catalytic inhibitor.The structure of the heterocyclic rings of these zwitterionic compounds is a factor of critical importance for interaction with GABA receptors. The present structure‐activity analysis demonstrates that heterocyclic GABA analogues having a high degree of delocalization of the negative charges have low affinity for the GABA receptors.

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Microelectrophoretic methods were used to study the effects on cat spinal neurones of a number of compounds structurally related to the gamma-aminobutyric acid (GABA) agonists muscimol, THIP, and isoguvacine. While N-methylmuscimol was an agonist at bicuculline methochloride-sensitive GABA receptors, somewhat weaker than GABA and THIP, neither N,N-dimethylmuscimol nor N-methyl-THIP interfered significantly with GABA receptors in vivo or binding sites in vitro. Both N,N-dimethylmuscimol and N-methyl-THIP, however, reversibly antagonized the depressant action of glycine. The seven-membered ring analogues of THIP, namely THIA (5,6,7,8-tetrahydro-4H-isoxazolo[5,4-c]azepin-3-ol), THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol) and iso-THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[3,4-d]azepin-3-ol), also blocked neuronal inhibition by glycine, iso-THAZ being the most potent compound. The conformationally mobile isomer of THAZ and iso-THAZ, 3-PYOL (5-(3-pyrrolidinyl)-3-isoxazolol), was a much less selective glycine antagonist, being also an antagonist of GABA, 3,4-TAZA (2,5,6,7-tetrahydro-1H-azepine-4-carboxylic acid) and 4,5-TAZA (2,3,6,7-tetrahydro-1H-azepine-4-carboxylic acid), which are amino acid analogues of THIA and THAZ, respectively, and ring homologues of isoguvacine, were also shown to be glycine antagonists. The mechanism of action of the present class of zwitterionic glycine antagonists is unknown. The compounds are much less potent than strychnine.

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