L-DOPA cyclohexyl ester is a novel potent and relatively stable competitive antagonist against L-DOPA among several L-DOPA ester compounds.
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.
Furukawa
N
N
Department of Pharmacology, Yokohama City University School of Medicine, Japan.
Goshima
Y
Y
Miyamae
T
T
Sugiyama
Y
Y
Shimizu
M
M
Ohshima
E
E
Suzuki
F
F
Arai
N
N
Fujita
K
K
Misu
Y
Y
D000818:Animals; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D007980:Levodopa / Q000037:antagonists & inhibitors*; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D018696:Neuroprotective Agents; D018698:Glutamic Acid; D007980:Levodopa