Delineation of the Role of Astroglial GABA Transporters in Seizure Control

Studies of GABA transport in neurons and astrocytes have provided evidence that termination of GABA as neurotransmitter is brought about primarily by active transport into the presynaptic, GABAergic nerve endings. There is, however, a considerable transport capacity in the astrocytes surrounding the synaptic terminals, a transport which may limit the availability of transmitter GABA leading to a higher probability of seizure activity governed by the balance of excitatory and inhibitory neurotransmission. Based on this it was hypothesized that selective inhibition of astrocytic GABA transport might prevent such seizure activity. A series of GABA analogs of restricted conformation were synthesized and in a number of collaborative investigations between Prof. Steve White at the University of Utah and medicinal chemists and pharmacologists at the School of Pharmacy and the University of Copenhagen, Denmark, GABA analogs with exactly this pharmacological property were identified. The most important analogs identified were N-methyl-exo-THPO (N-methyl-3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole) and its lipophilic analog EF-1502 ((RS)-4-[N-[1,1-bis(3-methyl-2-thienyl)but-1-en-4-yl]-N-methylamino]-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) both of which turned out to be potent anticonvulsants in animal models of epilepsy.