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We explore stable potent competitive antagonists against L-DOPA. In anesthetized rats, DOPA cyclohexyl ester (DOPA CHE) (30-100 ng) microinjected in depressor sites of the nucleus tractus solitarii dose-dependently shifted the dose-response-curve for L-DOPA (18-300 ng) to the right, with DOPA CHE (100 ng)-induced slight reduction of the maximum response. DOPA methyl ester (DOPA ME) at 100 ng also produced competitive antagonism. Antagonistic activity of DOPA CHE (100 ng) was similar to that of DOPA ME (300 ng). DOPA CHE is suitable for the purpose of screening.

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 μg 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 μg, 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 μΜ 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.

The effects of L-nitro-arginine (LNAG) and phorbol myristate acetate (PMA) were studied in bradykinin-induced relaxations in bovine coronary arteries. In the presence of indomethacin (10 microM), neither LNAG (100 microM) nor PMA (0.1 microM) inhibited the bradykinin-induced relaxations in coronary arterial rings contracted with prostaglandin F2 alpha. However, simultaneous application of LNAG and PMA almost completely abolished the bradykinin-induced relaxation. In a sandwich-method, endothelium-intact coronary arteries (donor vessels) were treated with LNAG or with PMA for 30 min and then placed in close apposition to a denuded ring (assay vessel). Pretreatment of the donor vessels with LNAG, but not with PMA, almost completely abolished the bradykinin-induced relaxations in the assay vessel. In contrast, treatment of the assay vessel with PMA or with LNAG had no effect. These results suggest that bradykinin-induced endothelium-dependent relaxation of bovine coronary artery depends on both the release of nitric oxide and other endothelium-derived relaxing factor(s), which is an extremely labile substance(s), or a non-diffusible factor(s). PMA seems to inhibit the production and/or the release of the latter substance(s).