Halogenated and isosteric cytisine derivatives with increased affinity and functional activity at nicotinic acetylcholine receptors
- 作者：Fitch ; Richard W. ; Kaneko ; Yumika ; Klaperski ; Paul ; Daly ; John W. ; Seitz ; Gunther ; G脙脙ndisch ; Daniela
- 关键词：Nicotinic receptors ; Cytisine ; Acetylcholine ; Structure脙脙脙脙脙脙activity relationships
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2005
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：February 15, 2005
- 卷：15
- 期：4
- 页码：1221-1224
- 文件大小：136 K
摘要
A series of pyridone ring-modified derivatives of (7R,9S)-(芒芒芒)-cytisine were evaluated for affinity and functional activity at neuromuscular 芒芒1芒芒1芒芒芒芒, ganglionic 芒芒3芒芒4, and central neuronal 芒芒4芒芒2 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 芒芒4芒芒2 subtype.