Nobuya Furukawa1,2, Yoshio Goshima1, Takeaki Miyamae1,
Minako Shimizu3, Etsuo Ohshima4, Fumio Suzuki4, Nobutaka Arai5,
Kiyohide Fujita2 and Yoshimi Misu1,6,*
Departments of 1Pharmacology and 2Oral and Maxillofacial Surgery,
Yokohama City University School of Medicine, Yokohama 236–0004, Japan
3Departmentof Pharmacology, Kyoritsu College of Pharmacy, Tokyo 105–0011, Japan
4Drug Discovery Laboratories, Pharmaceutical Research Institute, Kyowa Hakkou Co., Ltd., Shizuoka 411–8731, Japan
5Department for Neuroscience, Tokyo Metropolitan Institute of Neuroscience, Tokyo 183–8526, Japan
6Shinobu Hospital, Fukushima 960–1101, Japan
*Address correspondence to Dr.Y.Misu at Shinobu Hospital, Fukushima 960–1101, Japan.
*Reprint requests to Dr.Y.Misu at Department of Pharmacology, Yokohama City University School of Medicine, Yokohama 236–0004, Japan.
Abstract: 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 microg microinjected into depressor sites of the nucleus tractus solitarii elicited or tended to elicit more marked antagonism against depressor responses to 60ng L–DOPA, compared to DOPA ME. At 100 ng, DOPA CHE elicited the most potent antagonism. At 1 microg, 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 microgM 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, dopaminergicD1 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.
Keywords: DOPA cyclohexyl ester, Competitive L–DOPA antagonist, Nucleus tractus solitarii,
Nucleus accumbens, Glutamatergic and dopaminergic binding