GABA‐A agonists and GABA uptake inhibitors: Structure‐activity relationships

Abstract

Muscimol is a potent but non-selective GABA-A agonist. Structure-activity studies on the (S)-and (/?)-forms of chiral muscimol analogues have disclosed a high degree of agonist stereoselectivity of the GABA-A receptors. THlP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-01) is a specific GABA-A agonist, which has been the subject of clinical studies in different groups of patients. Even minor alterations of the structure of THlP result in substantial or complete loss of GABA-A agonist activity. 4-PIOL (5-(4-piperidyl)isoxazol-3-ol) shows in vivo GABA-A agonist activity on spinal neurones, whereas the in vitro pharmacological effects in brain tissue preparations are consistent with a GABA-A antagonist profile of 4-PIOL in the brain. Whereas nipetcotic acid and related GABA uptake inhibitors are substrates for the neuronal and glial transport carriers, the glia-selective GABA uptake inhibitors THPO (4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol) and probably also THAO (5,6,7, 8-tetrahydro-4H-isoxazolo[4,5-c]azepin-3-oI) are not being transported by the glial uptake carrier. Introduction of the DPB (4,4-diphenyl-3-butenyl) or BEE (benzhydryl ethyl ether) substituents on the basic nitrogen atoms of GABA uptake inhibitors, including nipecotic acid and THPO, results in markedly more potent inhibitors. However, unlike THPO, N-DPB-THPO interacts non-selectively with neuronal and glial GABA uptake, and, in contrast to nipecotic acid, N-DPB-nipecotic acid (SKF-89976-A) has been shown not to be transported by the neuronal or glial GABA carriers. Whereas N-DPB-and N-BEE-GABA are weak inhibitors of synaptosomal GABA uptake, N-methylation of these compounds gives potent uptake inhibitors.

Selective Inhibitors of Glial GABA Uptake: Synthesis, Absolute Stereochemistry, and Pharmacology of the Enantiomers of 3-Hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (exo-THPO) and Analogues

“…The 3-isoxazolol bioisostere of these amino acids, THPO ( 1 ), on the other hand, has been shown not to be a substrate for the glial GABA transporter, and although 1 is only a weak inhibitor of GABA uptake, it shows potent anticonvulsant effects after intracerebroventricular administration in animals . These effects of 1 have been associated with its weak but significant selectivity for the glial GABA uptake systems and its lack of ability to act as a substrate for this GABA transporter. − …”

Synthesis of Novel GABA Uptake Inhibitors. 3. Diaryloxime and Diarylvinyl Ether Derivatives of Nipecotic Acid and Guvacine as Anticonvulsant Agents

“…The most potent of these, 5 (Chart ), has a diarylpropyl system bonded directly to a carbon of the cyclic amino acid and exhibits in vitro potency similar to that of 3 . Compound 6 (Chart ), an analogue of 3 containing a hydroxyisoxazole as an acid isostere, exhibited a certain degree of seizure suppression in vivo. The triphenylmethyl derivative 7 (Chart ), with some structural similarity to 2 , has been shown to have micromolar affinity for the GABA transporter type 4 (GAT-4) …”

GABA and Glutamate Receptors as Therapeutic Targets in Neurodegenerative Disorders*

“…The apparent reduction of BZD binding by 4-PIOL seen at low temperature and in the absence of chloride ions, probably reflects blockade of the stimulatory effects of the very low concentrations of residual GABA, which remains following preparation of the brain synaptic membranes. The effects of 4-PIOL on muscimol-induced stimulation of diazepam binding are very similar to those of the GABAA antagonist bicuculline methochloride (BMC) (Falch et al 1990) (fig. 3).…”