A new class of GABA agonist

Abstract

COMPOUNDS which mimic the activity of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) on postsynaptic receptors are of particular pharmacological interest as possible therapeutic agents in human neurological disorders and as molecular probes with which to study different types of GABA receptors. The GABA molecule has considerable flexibility with free rotation around all three carbon–carbon bonds as indicated in Fig. 1. This conformational mobility is reduced in GABA analogues such as trans-4-aminocrotonic acid¹ and muscimol², which are potent GABA agonists at bicuculline-sensitive receptors on spinal neurones of the cat. The conformational mobility of such compounds can be reduced still further by incorporating the amino function in a ring structure. This has led to a new class of GABA agonist described here, based on l,2,3,6-tetrahydropyridine-4-carboxylic acid (isoguvacine) and the related bicyclic isoxazole 4,5,6,7-tetra-hydroisoxazolo[5,4-c]pyridin-3-ol (THIP) (Fig. 1). Isoguvacine represents a semi-rigid analogue of trans-4-aminocrotonic acid in a folded conformation. THIP, a folded analogue of muscimol, is even more rigid as the ‘masked’ carboxyl group (the 3-isoxazolo moiety) is fixed in the general plane of the molecule. The action of these compounds as GABA agonists provides indirect evidence that GABA interacts with bicuculline-sensitive postsynaptic receptors in the cat spinal cord in a partially extended and almost planar conformation.