We explored
L-DOPA esters with chemically bulky structures to find a potent stable competitive antagonist against
L-DOPA, compared to
DOPA methyl
ester (
DOPA ME). In anesthetized rats,
DOPA cyclohexyl
ester (
DOPA CHE),
DOPA cyclopentyl
ester (
DOPA CPE) and
DOPA cyclopentyldimethyl
ester (
DOPA CPDME) at 1 microgram microinjected into depressor sites of the nucleus tractus solitarii elicited or tended to elicit more marked antagonism against depressor responses to 60 ng
L-DOPA, compared to
DOPA ME. At 100 ng,
DOPA CHE elicited the most potent antagonism. At 1 microgram, duration of the antagonistic activity of
DOPA CHE was approximately three times longer than that of
DOPA ME. During microdialysis of the nucleus accumbens, conversion from
DOPA CHE at 1 microM perfused via probes to extracellular
L-DOPA was the lowest among these compounds and less than one half of that from
DOPA ME. Binding studies showed that the recognition site for
L-DOPA differs from ionotropic glutamatergic, dopaminergic D1 and D2 receptors. We recently found that
L-DOPA evoked by transient
ischemia may act as a
DOPA CHE-sensitive causal factor for
glutamate release and resultant neuronal cell death.
DOPA CHE is the most potent, relatively stable competitive antagonist against
L-DOPA and is a useful mother compound to develop
neuroprotective drugs.