Irreversible inhibitors of nicotinic acetylcholine receptors: isolation and structural characterization of the biologically active solvolysis products of bipinnatin-A and bipinnatin-C.
Irreversible inhibitors of nicotinic acetylcholine receptors: isolation and structural characterization of the biologically active solvolysis products of bipinnatin-A and bipinnatin-C.
复制标题
烟碱乙酰胆碱受体的不可逆抑制剂：bipinnatin-A 和 bipinnatin-C 生物活性溶剂分解产物的分离和结构表征。
DOI：
10.1021/jm00012a023
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发表时间：
1995
影响因子：
7.3
通讯作者：
Abramson,SN
中科院分区：
文献类型：
--
作者：
Hyde,EG;Boyer,A;Tang,P;Xu,Y;Abramson,SN
这种毒素通过共价修饰受体α亚基中的酪氨酸190，不可逆转地抑制烟碱乙酰胆碱受体。先前的研究表明，自然产生的钩虫毒素类似物bipinnatin-A、-B和-C实际上是非活性的原毒素，它们不可逆转地抑制尼古丁受体的能力通过在缓冲液中预先孵育而增强。然而，在缓冲液中预先孵育似乎并不能增强毒素不可逆地抑制烟碱受体的能力。这些观察结果导致了目前分离和确定具有生物活性的联苯纳豆素结构的努力。褐飞虱毒素从溶液中的消失率服从简单的一级指数衰减函数。然而，钩端螺旋藻毒素的稳定性大约是联品蛋白-A、-B或-C的40倍。联苯那丁素的溶解，而不是钩端螺旋藻毒素的溶解，产生等摩尔量的醋酸的速度与溶解的速度相似，这表明这些毒素在溶解中的初始事件涉及醋酸酯的水解。用质子核磁共振谱和快原子轰击质谱仪确证了联品素-A和-C的活性溶剂分解产物的结构。它们的结构和溶解反应的相对pH不敏感性表明，生物活化可能是通过SNI类型的取代反应进行的，该反应包括消除醋酸酯，然后碳正离子中间体与溶剂的反应。
The lophotoxins irreversibly inhibit nicotinicacetylcholine receptors by covalent modification of Tyr190 in the a-subunits of the receptor. Previous studies have shown that the naturally occurring lophotoxin analogs bipinnatin-A,-B, and-C are actually inactive protoxinsand that their ability to irreversibly inhibit nicotinic receptors is enhanced by preincubation in buffer. However, the ability of lophotoxinto irreversibly inhibit nicotinic receptors does not appear to be enhanced bypreincubation in buffer. These observations led tothe current effort to isolate and determine the structures of biologicallyactive bipinnatins. Disappearance of the lophotoxins from solution followed a simple first-order exponential decay function. Lophotoxin, however, was approximately 40-fold more stable thenbipinnatin-A,-B, or-C. Solvolysis of the bipinnatins, but not of lophotoxin, resulted in production of an equimolar amount of acetic acid at a rate similar to the rate of solvolysis, suggesting that the initial event in solvolysis of these toxins involveshydrolysis of an acetate ester. Proton NMR and fast-atom bombardment mass spectroscopy were used toconfirm the structures of the active solvolysis products of bipinnatin-A and-C. Their structures and the relative pH insensitivity of the solvolysis reaction suggest that biological activation of the bipinnatins may proceed through an SnI type of substitution reaction involving elimination of acetate followed by reactionof a carbocation intermediate with solvent.