Halogenated and isosteric cytisine derivatives with increased affinity and functional activity at nicotinic acetylcholine receptors.
Halogenated and isosteric cytisine derivatives with increased affinity and functional activity at nicotinic acetylcholine receptors.
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DOI：
10.1016/j.bmcl.2004.11.073
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发表时间：
2005-02
影响因子：
2.7
通讯作者：
R. Fitch;Yumika Kaneko;Paul Klaperski;J. Daly;G. Seitz;D. Gündisch
中科院分区：
文献类型：
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作者：
R. Fitch;Yumika Kaneko;Paul Klaperski;J. Daly;G. Seitz;D. Gündisch
研究了一系列吡啶酮环修饰的(7R，9S)-(−)-胱氨酸衍生物在神经肌型α1β1γδ、神经节α3β4和中枢神经元α4β2亚型烟碱受体上的亲和力和功能活性。3-位的卤代反应提高了亲和力和功能活性，5-位的取代导致两者略有下降，二取代导致功能活性几乎被取消，并可能与卤素的吸电子能力有关。卤代衍生物的亚型选择性相对于胱氨酸以取代依赖的方式改变。甲碘茶碱的药效弱于胞苷，但仍具有显著的活性。硫代胞苷的效力和疗效相对较弱，但对α4β2亚型有明显的选择性。
A series of pyridone ring-modified derivatives of (7R,9S)-(−)-cytisine were evaluated for affinity and functional activity at neuromuscular α1β1γδ, ganglionic α3β4, and central neuronal α4β2 subtypes of nicotinic receptors. Halogenation at the 3-position improved affinity and functional activity, while substitution at the 5-position led to modest decreases in both, and disubstitution led to near abolition of functional activities and could be correlated with the electron-withdrawing ability of the halogen. Subtype selectivities of the halogenated derivatives were altered relative to cytisine in a substitution-dependent manner. Caulophylline methiodide was less potent than cytisine, but retained significant activity. Thiocytisine was relatively weak in potency and efficacy, but was significantly selective for the α4β2 subtype.