4-aminotetrolic acid: new conformational-restricted analogue of -aminobutyric acid.

Abstract

RECENT studies strongly support a role for γ-aminobutyric acid (GABA) as an inhibitory transmitter at certain synapses in the mammalian central nervous system. Structure activity correlations of many GABA analogues implicate both the intramolecular distance between the zwitterionic centres and the rotational freedom of the molecule as important factors governing the synaptic activity of these substances1. The following observations provide pertinent information about the active conformation(s) of GABA recognized by the receptor. (1) Muscimol, an isoxazole isolated from Amanita muscaria, seems to function as a GABA analogue as its inhibitory action on central neurones is comparable with that of GABA both in potency2 and with respect to antagonism by bicuculline3. Molecular orbital calculations suggest that GABA and muscimol can assume similar conformations as zwitterions with the charged centres (N+ and 0−) at least 5 and, more likely, 6 A apart4. (2) The selective GABA antagonist bicuculline exhibits some degree of structural similarity with particular conformations of GABA and muscimol3. (3) X-ray crystallography indicates that GABA exists in a partially folded conformation in the solid state5,6. (4) A model of the GABA receptor proposes that GABA adopts a folded conformation with a distance of less than 4.4 A between the charged centres7. Observations (1) and (2) suggest extended conformations for GABA, while (3) and (4) suggest folded conformations.