Structure and Biological Activity of a Series of Conformationally Restricted Analogues of Gaba

Abstract

—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. 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.

2-Methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-ol monohydrate, a structural analogue of THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol)

“…compound, a comprehensive series of heterocyclic GABA analogues has been developed (KrogsgaardLarsen, 1978;Krogsgaard-Larsen, Honor6 & Thyssen, 1979;Brehm, Krogsgaard-Larsen & Jacobsen, 1979) and studied with respect to various GABA synaptic processes (Krogsgaard-Larsen, Johnston, Curtis, Game & McCulloch, 1975;, 1978. Some muscimol analogues including THIP are very potent GABA agonists in vivo and in vitro (Krogsgaard-Larsen, Johnston, Lodge & Curtis, 1977).…”

“…is a very active and selective GABA (~,-aminobutyric acid) agonist (Johnston, Curtis, DeGroat & Duggan, 1968;Curtis, Duggan, Felix & Johnston, 1971;Krogsgaard-Larsen, Johnston, Curtis, Game & McCulloch, 1975). Using muscimol as a model 0567-7408/82/102741-04501.00…”

What confers specificity on glycine for its receptor site?

“…2 Author for correspondence. (Krogsgaard-Larsen et al, 1975;Johnston et al, 1976). Similarly, the ability of acetylcholine to exist in different conformational states, accounts for its ability to activate either nicotinic or muscarinic receptors.…”

Muscimol injections in the nucleus raphé dorsalis block the antinociceptive effect of morphine in rats: apparent lack of 5‐hydroxytryptamine involvement in muscimol's effect

“…Injections of muscimol, a y-aminobutyric acid (GABA) receptor agonist (Krogsgaard-Larsen, Johnston, Curtis, Game & McCulloch, 1975), in the raphe nuclei dorsalis (DR) and medianus (MR) have been recently reported to reduce 5-hydroxytryptamine (5-HT) metabolism in the striatum and hippocampus respectively of rats (Przewlocka, Stala & Scheel-Kruger, 1979;Forchetti & Meek, 1981). These findings suggest that muscirnol injection in the raphe nuclei inhibits the activity of 5-HT neurones originating in these brain areas (Przewlocka et al, 1979;Forchetti & Meek, 1981).…”