R.M. McCulloch

STRUCTURE AND BIOLOGICAL ACTIVITY OF A SERIES OF CONFORMATIONALLY RESTRICTED ANALOGUES OF GABA

—Microelectrophoretic methods were used to study the effects on spinal neurones of a series of conformationally restricted analogues of GABA, most of which are structurally related to musci‐mol (3‐hydroxy‐5‐aminomethylisoxazole). 3‐Hydroxy‐5‐(l‐aminoethyl)isoxazole and 3‐hydroxy‐5‐(2‐aminoethyl)isoxazole were GABA‐like depressants comparable in effectiveness with GABA. The inhibitors of GABA uptake 4,5,6,7‐tetrahydroisoxazolo[4,5‐c]pyridin‐3‐ol and nipecotic acid (piperidine‐3‐carboxylic acid) reversibly enhanced the depressant action of GABA. 3‐Hydroxy‐5‐dimethylaminomethly‐isoxazole, 5,6,7,8‐tetrahydro‐4H‐isoxazolo[4,5‐d]azepm‐3‐ol, 4,5,6,7‐tetrahydroisoxazolo[4,5‐c]pyridin‐3‐ol, and nipecotic acid reversibly antagonized the postsynaptic action of glycine.

Central effects of β-(p-chlorophenyl)-γ-aminobutyric acid

(1) Electrophoretically administered β-(p-chlorophenyl)-GABA depressed the firing of spinal interneurones, pyramidal tract neurones and Purkinje cells of anaesthetised cats. Although less potent than GABA, the action of β-p-CPG was more prolonged. (2) Renshaw cells were relatively insensitive to β-p-CPG. (3) Since the depressant effects of β-p-CPG were not reduced by either biculline methochloride or strychnine, activation of GABA or glycine receptors seems an unlikely explanation of the depressant action. (4) β-p-CPG inhibited GABA transaminase activity and reduced the high affinity uptake ofl-glutamate by rat brain slices. (5) β-p-CPG may activate neuronal receptors for an inhibitory transmitter chemically related to phenylethylamine.

Cis- and trans-4-aminocrotonic acid as GABA analogues of restricted conformation.

Cis‐4‐aminocrotonic acid, an analogue of GABA in a folded conformation, appears not to act as a GABA analogue with respect to bicuculline‐sensitive postsynaptic receptors, ‘high affinity’ GABA uptake and GABA: 2‐oxoglutarate aminotransferase in the mammalian central nervous system. On the other hand, trans‐4‐aminocrotonic acid, an analogue of GABA in an extended conformation, acts as efficiently as GABA with respect to each of the above systems, indicating that extended rather than folded conformations of GABA are likely to be important in the interaction of GABA with the specific macromolecules concerned.

The differential sensitivity of spinal interneurones and Renshaw cells to kainate and N-methyl-D-aspartate

SummaryWith sensitivity to N-methyl-D-aspartate as the basis for comparison, spinal interneurones were relatively more sensitive than Renshaw cells to kainate, a conformationally restricted analogue of glutamate. These findings are consistent with proposed transmitter roles for L-glutamate and L-aspartate in the spinal cord.

ANTAGONISM OF INHIBITORY AMINO ACID ACTION BY TUBOCURARINE

A comparison has been made of the antagonism by microelectrophoretically administered (+)‐tubocurarine, bicuculline methochloride and strychnine of the inhibition of spinal interneurones and Renshaw cells in the cat by glycine and γ‐aminobutyric acid. The results indicate that (+)‐tubocurarine would be of little use in assessing which of these amino acids was the transmitter at central inhibitory synapses.