甘氨酸前体药物米拉醋胺（2-N-戊基氨基乙酰胺）对离体肾上腺髓质嗜铬细胞儿茶酚胺分泌的影响。

Effects of the glycine prodrug milacemide (2-N-pentylaminoacetamide) on catecholamine secretion from isolated adrenal medulla chromaffin cells.

Yadid G, Zinder O, Youdim M B

Department of Pharmacology, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa.

Br J Pharmacol. 1991 Nov;104(3):760-4. doi: 10.1111/j.1476-5381.1991.tb12501.x.

Abstract

Milacemide (2-n-pentylaminoacetamide) is a glycine prodrug which readily crosses the blood brain barrier and increases brain glycine and glycineamide. In vitro and in vivo studies, with numerous tissues, including adrenal chromaffin cells, have clearly shown that the formation of the latter metabolites is exclusively mediated by monoamine oxidase B for which milacemide is a substrate. 2. Milacemide, glycineamide and glycine caused a time- and dose-dependent release of catecholamines from bovine isolated chromaffin cells. 3. Milacemide (10(-4) M) induced catecholamine release was roughly 30% of that initiated by acetylcholine (10(-4) M), the natural secretagogue. 4. The combined effects of milacemide (10(-4) M) and acetycholine (10(-4) M) on catecholamine secretion from chromaffin cells is additive, suggesting that milacemide does not act through the normal nicotinic receptor release mechanism. 5. The release of catecholamines from chromaffin cells in response to milacemide (10(-4) M) was partially inhibited by the selective MAO-B inhibitors (-)-deprenyl (10(-7) M) and AGN 1135 (10(-6) M). This indicates that the MAO-B derived metabolites, glycineamide and glycine, contribute to the secretion of catecholamines as does milacemide itself. 6. It is apparent that release of catecholamines by glycine is mediated by its uptake into the cells since [3H]-glycine uptake and catecholamine release showed a highly significant correlation (r = 0.96).

摘要

米拉美胺（2 - 正戊基氨基乙酰胺）是一种甘氨酸前体药物，它能轻易穿过血脑屏障并增加脑内甘氨酸和甘氨酰胺的含量。包括肾上腺嗜铬细胞在内的众多组织的体外和体内研究均清楚表明，后一种代谢产物的形成完全由单胺氧化酶B介导，米拉美胺是该酶的底物。2. 米拉美胺、甘氨酰胺和甘氨酸可引起牛离体嗜铬细胞中儿茶酚胺呈时间和剂量依赖性释放。3. 米拉美胺（10⁻⁴ M）诱导的儿茶酚胺释放量约为天然促分泌剂乙酰胆碱（10⁻⁴ M）引发释放量的30%。4. 米拉美胺（10⁻⁴ M）和乙酰胆碱（10⁻⁴ M）对嗜铬细胞儿茶酚胺分泌的联合作用是相加的，这表明米拉美胺并非通过正常的烟碱样受体释放机制起作用。5. 选择性单胺氧化酶B抑制剂（ - ） - 司来吉兰（10⁻⁷ M）和AGN 1135（10⁻⁶ M）可部分抑制米拉美胺（10⁻⁴ M）引起的嗜铬细胞儿茶酚胺释放。这表明单胺氧化酶B衍生的代谢产物甘氨酰胺和甘氨酸与米拉美胺本身一样，都有助于儿茶酚胺的分泌。6. 显然，甘氨酸引起的儿茶酚胺释放是由其摄取进入细胞介导的，因为[³H] - 甘氨酸摄取与儿茶酚胺释放显示出高度显著的相关性（r = 0.96）。