Jpn. J. Pharmacol. 82 (1), 40-47 (2000)

LﾐDOPA Cyclohexyl Ester Is a Novel Potent
and Relatively Stable Competitive Antagonist
Against LﾐDOPA Among Several LﾐDOPA Ester Compounds

Nobuya Furukawa^1,2, Yoshio Goshima¹, Takeaki Miyamae¹, Yoshinobu Sugiyama¹,
Minako Shimizu³, Etsuo Ohshima⁴, Fumio Suzuki⁴, Nobutaka Arai⁵,
Kiyohide Fujita² and Yoshimi Misu^1,6,*


Departments of ¹Pharmacology and ²Oral and Maxillofacial Surgery,
Yokohama City University School of Medicine, Yokohama 236ﾐ0004, Japan
³Departmentof Pharmacology, Kyoritsu College of Pharmacy, Tokyo 105ﾐ0011, Japan
⁴Drug Discovery Laboratories, Pharmaceutical Research Institute, Kyowa Hakkou Co., Ltd., Shizuoka 411ﾐ8731, Japan
⁵Department for Neuroscience, Tokyo Metropolitan Institute of Neuroscience, Tokyo 183ﾐ8526, Japan
⁶Shinobu Hospital, Fukushima 960ﾐ1101, Japan
*Address correspondence to Dr.Y.Misu at Shinobu Hospital, Fukushima 960ﾐ1101, Japan.
*Reprint requests to Dr.Y.Misu at Department of Pharmacology, Yokohama City University School of Medicine, Yokohama 236ﾐ0004, Japan.

Abstract: We explored LﾐDOPA esters with chemically bulky structures to find a potent stable competitive antagonist against Lﾐ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ﾐ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ﾐ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ﾐDOPA differs from ionotropic glutamatergic, dopaminergicD₁ and D₂ receptors. We recently found that LﾐDOPA evoked by transient ischemia may act as a DOPA CHEﾐsensitive causal factor for glutamate release and resultant neuronal cell death. DOPA CHE is the most potent, relatively stable competitive antagonist against LﾐDOPA and is a useful mother compound to develop neuroprotective drugs.

Keywords: DOPA cyclohexyl ester, Competitive LﾐDOPA antagonist, Nucleus tractus solitarii,
Nucleus accumbens, Glutamatergic and dopaminergic binding