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A series of lipophilic diaromatic derivatives of the glia-selective GABA uptake inhibitor (
R)-4-amino-4,5,6,7-tetrahydrobenzo[
d]isoxazol-3-ol [(
R)-
exo-THPO,
4] were synthesized via reductive amination of 3-ethoxy-4,5,6,7-tetrahydrobenzo[
d]isoxazol-4-one (
9) or via
N-alkylation of
O-alkylatedracemic
4. The effects of the target compounds on GABA uptake mechanisms in vitro were measured using a rat brain synaptosomal preparation or primary cultures of mouse cortical neurons and glia cells (astrocytes), as well as HEK cells transfected with cloned mouse GABA transporter subtypes (GAT1-4). The activity against isoniazid-induced convulsions in mice after subcutaneous administration of the compounds was determined. All of the compounds were potent inhibitors of synaptosomal uptake the most potent compound being (
RS)-4-[
N-(1,1-diphenylbut-1-en-4-yl)amino]-4,5,6,7-tetrahydrobenzo[
d]isoxazol-3-ol (
17a, IC
50
=
0.14
μM). The majority of the compounds showed a weak preference for glial, as compared to neuronal, GABA uptake. The highest degree of selectivity was 10-fold corresponding to the glia selectivity of (
R)-
N-methyl-
exo-THPO (
5). All derivatives showed a preference for the GAT1 transporter, as compared with GAT2-4, with the exception of (
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 (
28d), which quite surprisingly turned out to be more potent than GABA at both GAT1 and GAT2 subtypes. The GAT1 activity was shown to reside in (
R)-
28d whereas (
R)-
28d and (
S)-
28d contributed equally to GAT2 activity. This makes (
S)-
28d a GAT2 selective compound, and (
R)-
28d equally effective in inhibition of GAT1 and GAT2 mediated GABA transport. All compounds tested were effective as anticonvulsant reflecting that these compounds have blood–brain barrier permeating ability.