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

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  • Furukawa Nobuya
    Departments of Pharmacology,Yokohama City University School of Medicine,Yokohama 236-0004,Japan Dapartment of Oral and Maxillofacial Surgery,Yokohama City University School of Medicine,Yokohama 236-0004,Japan
  • Goshima Yoshio
    Departments of Pharmacology,Yokohama City University School of Medicine,Yokohama 236-0004,Japan
  • Miyamae Takeaki
    Departments of Pharmacology,Yokohama City University School of Medicine,Yokohama 236-0004,Japan
  • Sugiyama Yoshinobu
    Departments of Pharmacology,Yokohama City University School of Medicine,Yokohama 236-0004,Japan
  • Shimizu Minako
    Department of Pharmacology,Kyoritsu College of Pharmacy,Tokyo 105-0011,Japan
  • Ohshima Etsuo
    Drug Discovery Laboratories,Pharmaceutical Research Institute,Kyowa Hakkou Co.,Ltd.,Shizuoka 411-8731,Japan
  • Suzuki Fumio
    Drug Discovery Laboratories,Pharmaceutical Research Institute,Kyowa Hakkou Co.,Ltd.,Shizuoka 411-8731,Japan
  • Arai Nobutaka
    Department for Neuroscience,Tokyo Metropolitan Institute of Neuroscience,Tokyo 183-8526,Japan
  • Fujita Kiyohide
    Dapartment of Oral and Maxillofacial Surgery,Yokohama City University School of Medicine,Yokohama 236-0004,Japan
  • Misu Yoshimi
    Departments of Pharmacology,Yokohama City University School of Medicine,Yokohama 236-0004,Japan Shinobu Hospital,Fukushima 960-1101,Japan

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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 1μg 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, compard to DOPA ME.At 100 ng, DOPA CHE elicited the most potent antagonism.At 1μg, 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 1μM 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.

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