PHARMACOLOGICALLY ACTIVE COMPOUNDS FROM AMPHIBIANS AND OTHER NATURAL SOURCES

来自两栖动物和其他天然来源的药理活性化合物

• 批准号: 3917733
• 负责人: J W DALY
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3917733
• 关键词: Anura; X ray crystallography; alkaloids; allosteric site; animal poison; aquatic organism; batrachotoxins; bioassay; calcium metabolism; cardiotonic agents; chemical structure function; fresh water environment; gas chromatography; heart pharmacology; high performance liquid chromatography; indolizines; ion transport; local anesthetics; mass spectrometry; muscle pharmacology; muscle relaxants; neuropharmacology; neurotoxins; nicotinic receptors; nuclear magnetic resonance spectroscopy; pheochromocytoma; piperidine; potassium channel; saltwater environment; skin; sodium channel; thin layer chromatography

Natural products have provided a wide range of biologically active agents, many of which have unique profiles of pharmacological activity and therapeutic potential. Over two hundred alkaloids have been identified in extracts from amphibian skins. These include batrachotoxins, which are potent activators of sodium channels, histrionicotoxins. which are noncompetitive blockers of nicotinic receptor channel complexes and of potassium channels, and pumiliotoxins, which have myotonic and cardiotonic activity due to inhibitory effects on closing of sodium channels. Pumiliotoxin B acts at a specific site on the sodium channel to increase sodium flux and augments the effects of other sodium channel agents, such as the scorpion toxins and brevetoxins. Structure activity relationships indicate a stereoselective interaction with the side chain hydroxy groups of the pumiliotoxin alkaloids. Local anesthetics inhibit the stimulatory effects of batrachotoxin on both sodium flux and phosphoinositide breakdown in brain synaptoneurosomes. In addition, local anesthetics stimulate incorporation of inositol into phosphoinositides. A 5-substituted- 8-methylindolizidine markedly enhances and then at higher concentrations inhibits binding of radioactive perhydrohistrionicotoxin to the nicotinic receptor-channel complex. It has agonist activity at nicotinic receptors of pheochromocytoma cells. Other dendrobatid alkaloids, such as both the cis- and trans-2,5-disubstituted decahydroquinolines, the 3,5-disubstituted indolizidines, the 2,5-disubstituted pyrrolidines, the 2,6- disubstituted piperidines and a 2,6-disubstituted-4- hydroxypiperidine are potent inhibitors of binding of perhydrohistrionicotoxin and have noncompetitive antagonist activity at nicotinic receptors of pheochromocytoma cells. The biological activity of trace alkaloids from dendrobatid frogs, such as the azatricyclododecenes, the amidines and the homopumiliotoxins, and of the tricyclic indole alkaloids from myobatrachid frogs remain unknown. One amidine alkaloid is a potent analgetic.

天然产品提供了广泛的生物活性 代理，其中许多具有药理学独特的特征 活动和治疗潜力。 超过200个生物碱 已经在两栖皮肤的摘录中鉴定出来。 这些 包括脂肪毒素，它们是钠的有效激活剂 频道，trionionicotoxins。这是非竞争的阻滞剂 烟碱受体通道复合物和钾通道，以及 pumiliotodins，由于 对钠通道关闭的抑制作用。 pumiliotoxin b 在钠通道上的特定部位作用以增加钠 通量和增强其他钠通道剂的影响，例如 作为蝎子毒素和布雷毒素。 结构活动 关系表示与侧面的立体选择性相互作用 粉状毒素生物碱的链羟基。 当地的 麻醉剂抑制batrachotoxin对刺激作用 大脑中的钠通量和磷酸肌醇分解 Synaptoneurosomes。 此外，局部麻醉剂刺激 将肌醇掺入磷酸肌醇中。 一个5分取代的 8-甲基丁胺明显增强，然后在较高 浓度抑制放射性的结合 到烟碱受体通道复合物的perhidrohistionicotoxin。 它具有嗜铬细胞瘤的烟碱受体的激动剂活性 细胞。 其他树突生物碱，例如顺式和 trans-2,5取代的decahydroquinolines，3,5-均取代 吲哚苷，2,5二取代的吡咯烷，2,6-- 脱取代的哌啶和2,6-二取代-4-- 羟基吡啶定是结合的有效抑制剂 perhidrohistionicotoxin，具有非竞争性拮抗剂 在嗜铬细胞瘤细胞的烟碱受体上的活性。 这 来自树突青蛙的痕量生物碱的生物学活性， 作为AzatricyClododecenes，amidines和 同型蛋白毒素和三环吲哚生物碱的 myobatrachid蛙仍然未知。 一个amidine生物碱是 有效的肛门效果。