Discovery of a Potent and Selective 伪3尾4 Nicotinic Acetylcholine Receptor Antagonist from an 伪-Conotoxin Synthetic Combinatorial Library
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- 作者：Yi-Pin Chang ; Jayati Banerjee ; Cheryl Dowell ; Jinhua Wu ; Reena Gyanda ; Richard A. Houghten ; Lawrence Toll ; J. Michael McIntosh ; Christopher J. Armishaw
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：April 24, 2014
- 年：2014
- 卷：57
- 期：8
- 页码：3511-3521
- 全文大小：538K
- 年卷期：v.57,no.8(April 24, 2014)
- ISSN：1520-4804
文摘
伪-Conotoxins are disulfide-rich peptide neurotoxins that selectively inhibit neuronal nicotinic acetylcholine receptors (nAChRs). The 伪3尾4 nAChR subtype has been identified as a novel target for managing nicotine addiction. Using a mixture-based positional-scanning synthetic combinatorial library (PS-SCL) with the 伪4/4-conotoxin BuIA framework, we discovered a highly potent and selective 伪3尾4 nAChR antagonist. The initial PS-SCL consisted of a total of 113鈥?79鈥?04 sequences that were screened for 伪3尾4 nAChR inhibition, which facilitated the design and synthesis of a second generation library of 64 individual 伪-conotoxin derivatives. Eleven analogues were identified as 伪3尾4 nAChR antagonists, with TP-2212-59 exhibiting the most potent antagonistic activity and selectivity over the 伪3尾2 and 伪4尾2 nAChR subtypes. Final electrophysiological characterization demonstrated that TP-2212-59 inhibited acetylcholine evoked currents in 伪3尾4 nAChRs heterogeneously expressed in Xenopus laevis oocytes with a calculated IC50 of 2.3 nM and exhibited more than 1000-fold selectivity over the 伪3尾2 and 伪7 nAChR subtypes. As such, TP-2212-59 is among the most potent 伪3尾4 nAChRs antagonists identified to date and further demonstrates the utility of mixture-based combinatorial libraries in the discovery of novel 伪-conotoxin derivatives with refined pharmacological activity.