Open Accessl-DOPA Cyclohexyl Ester Is a Novel Potent and Relatively Stable Competitive Antagonist Against l-DOPA Among Several l-DOPA Ester Compounds
Author(s) -
Nobuya Furukawa,
Yoshio Goshima,
Takeaki Miyamae,
Yoshifumi Sugiyama,
Minako Shimizu,
Etsuo Ohshima,
Fumio Suzuki,
Nobutaka Arai,
Kiyohide Fujita,
Yoshimi Misu
Publication year - 2000
Publication title -
japanese journal of pharmacology/japanese journal of pharmacology
Language(s) - English
Resource type - Journals
eISSN - 1347-3506
pISSN - 0021-5198
DOI - 10.1254/jjp.82.40
Subject(s) - microdialysis , chemistry , pharmacology , antagonist , antagonism , dopaminergic , glutamate receptor , ionotropic effect , levodopa , competitive antagonist , dopamine , extracellular , receptor , medicine , biochemistry , parkinson's disease , disease
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.