Analogs of WIN 62,577 define a second allosteric site on muscarinic receptors
Analogs of WIN 62,577 define a second allosteric site on muscarinic receptors
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DOI：
10.1124/mol.62.6.1492
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发表时间：
2002-12-01
影响因子：
3.6
通讯作者：
Birdsall, NJM
中科院分区：
文献类型：
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作者：
Lazareno, S;Popham, A;Birdsall, NJM
Win 51,708(17-beta-hydroxy-17-alpha-ethynyl-5-alpha-androstano[3，2-b]pyrimido[1，2-a]benzimidazole)和Win 62,577(17-beta-hydroxy17-alpha-ethynyl-Delta(4)-androstano[3，2-b]pyrimido[1，2-a]benzimidazole)是大鼠NK1受体的强效中枢活性拮抗剂，而不是人的NK1受体。用平衡和非平衡放射配基结合的方法研究了这些化合物及其类似物与[H-3]N-甲基东莨菪碱([H-3]NMS)和未标记的乙酰胆碱(ACh)在M-1-M-4受体上的相互作用。计算结果与变构三元络合物模型的预测结果一致。Win化合物与未连接受体的对数亲和力在5到6.7之间，并与[H-3]NMS和ACh表现出正、负或中性协同作用，这取决于受体亚型和相互作用配体的性质。Win 62,577是M受体上ACh亲和力的变构增强剂。尽管Win 62,577和Win 51,708以变构方式相互作用，但并不影响[H-3]NMS与M-3受体的解离。某些类似物比Win 62,577有更高的亲和力，Win 62,577的截短形式，包括类固醇，也具有变构作用。一种类似物，17-beta-hydroxy-17-alpha-Delta(4)-androstano[3，2-b]吡啶并[2，3-b]吲哚(PG987)，具有加速[H-3]NMS解离的独特作用；其作用最大，是M-3受体的2.5倍。PG987和其他变构药物在[H-3]NMS与M-3受体解离过程中的相互作用表明，PG987可逆地结合到一个不同于加拉胺和士的宁结合的位置：相反，PG987似乎与KT5720、星形孢子素和Win 51,708结合在M-3受体上的相同位置。因此，除了与士的宁(可能还有另一种变构增强剂氯甲基马钱子碱)结合的变构部位外，在M-3受体上还有第二个不重叠的、药理上不同的变构部位，它也支持与ACh的正协同作用。
WIN 51,708 (17-beta-hydroxy-17-alpha-ethynyl-5-alpha-androstano[3,2-b]pyrimido[1,2-a]benzimidazole) and WIN 62,577 (17-beta-hydroxy17-alpha-ethynyl-Delta(4)-androstano[3,2-b]pyrimido[1,2-a]benzimidazole) are potent and centrally active antagonists at rat, but not human, NK1 receptors. The interactions of these compounds and some analogs with [H-3]N-methyl scopolamine ([H-3]NMS) and unlabeled acetylcholine (ACh) at M-1-M-4 muscarinic receptors have been studied using equilibrium and nonequilibrium radioligand binding methods. The results are consistent with the predictions of the allosteric ternary complex model. The WIN compounds have log affinities for the unliganded receptor in the range 5 to 6.7, and exhibit positive, negative, or neutral cooperativity with [H-3]NMS and ACh, depending on the receptor subtype and nature of the interacting ligands. WIN 62,577 is an allosteric enhancer of ACh affinity at M, receptors. Although interacting allosterically, WIN 62,577 and WIN 51,708 do not affect [H-3]NMS dissociation from M-3 receptors. Certain analogs have higher affinities than WIN 62,577, and truncated forms of WIN 62,577, including steroids, also act allosterically. One analog, 17-beta-hydroxy-17-alpha-Delta(4)-androstano[3,2 -b] pyrido [2,3-b] indole (PG987), has the unique effect of speeding [H-3]NMS dissociation; its largest effect, 2.5-fold, is at M-3 receptors. The interaction between PG987 and other allosteric agents on [H-3]NMS dissociation from M-3 receptors indicate that PG987 binds reversibly to a site distinct from that to which gallamine and strychnine bind: in contrast, PG987 seems to bind to the same site on M-3 receptors as KT5720, staurosporine, and WIN 51,708. Therefore, in addition to the allosteric site that binds strychnine (and probably chloromethyl brucine, another allosteric enhancer) there is a second, nonoverlapping, pharmacologically distinct allosteric site on M-3 receptors that also supports positive cooperativity with ACh.