GABA-A AGONISTS AND GABA UPTAKE INHIBITORS - STRUCTURE-ACTIVITY-RELATIONSHIPS

Muscimol is a potent but non‐selective GABA‐A agonist. Structure‐activity studies on the (S)‐ and (R)‐forms of chiral muscimol analogues have disclosed a high degree of agonist stereoselectivity of the GABA‐A receptors. THIP (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol) 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 THIP 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 carrier, 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‐ol) 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. Copyright © 1990 Wiley‐Liss, Inc.