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-tetrahydroisoxazolo4,5-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-isoxazolo4,5-d]azepm-3-ol, 4,5,6,7-tetrahydroisoxazolo4,5-c]pyridin-3-ol, and nipecotic acid reversibly antagonized the postsynaptic action of glycine. A structure-activity correlation was made in an indirect attempt to elucidate some comformational requirements for interaction of GABA with its postsynaptic receptor and the binding site of its uptake system. The results seem to indicate that different conformations of GABA are required for these interactions.