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The main pharmacological effects and acute toxicity of nicergoline (NCG, ester type), its 5 metabolites [1-DN (ester type), 1-MMDL, 1-OHMMDL, MDL (ergoline-alcohol type) and 5-BNA (bromonicotinic acid)], 2 decomposition products (1-MMDL and 5-BNA) and 2 impurities [1-DN and 5-CN (ester type)] were studied in animals. In mice, the acute intraperitoneal toxicity of 1-MMDL, 1-OHMMDL and 5-CN was similar to that of NCG (LD50 197.6 mg/kg). The toxicity of 1-DN, MDL and 5-BNA was approximately 2-fold, 2- fold and one half of NCG, respectively. These substances caused no delayed death. In protective effects against KCN- and adrenaline-induced death in mice when given i.p., 1-DN and 1-MMDL were less potent than NCG, and 1-CN was similar in potency to NCG. In competitive inhibitory effects on phenylephrine-induced contraction of isolated guinea pig vas deferens, 1-DN was less potent, 1-MMDL was much less potent and 5-CN was more potent than NCG. In an inhibitory effect on collagen-induced platelet aggregation in vitro using rat platelet-rich plasma, 1-DN and 5-CN were similar in activity to NCG and 1-MMDL was less active than NCG. On the other hand, 1-OHMMDL, MDL and 5-BNA were inactive in these experiments. In experiments on gross behavior, motor function and barbital anesthesia using mice, when given i.p., 5-CN as well as NCG moderately induced depressive effects on the central nervous systems. 1-DN and 1-MMDL were less potent in the effects than NCG. In anesthetized rats, when given i.v., 1-DN and 5-CN dose-dependently caused lowering effects on blood pressure similar to NCG. 1-MMDL and 1-OHMMDL were less potent than NCG in the lowering effect. 1-DN and 5-CN moderately decreased the contractile force in the isolated guinea pig heart when given i.a. 5-CN alone decreased urine volume in rats when given i.p. and all the substances had no effect on the intestinal transit ability in mice when given i.p. These results suggest that the pharmacological effects of NCG are due to NCG per se and in part to its metabolites. As regards structure-activity relationships, NCG, 1-DN and 5-CN with an ester linkage were found to be more potent in pharmacological activities than ergoline-alcohol compounds.(ABSTRACT TRUNCATED AT 400 WORDS)
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