Dicarba 伪-Conotoxin Vc1.1 Analogues with Differential Selectivity for Nicotinic Acetylcholine and GABAB Receptors
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- 作者：Bianca J. van Lierop ; Samuel D. Robinson ; Shiva N. Kompella ; Alessia Belgi ; Jeffrey R. McArthur ; Andrew Hung ; Christopher A. MacRaild ; David J. Adams ; Raymond S. Norton ; Andrea J. Robinson
- 刊名：ACS Chemical Biology
- 出版年：2013
- 出版时间：August 16, 2013
- 年：2013
- 卷：8
- 期：8
- 页码：1815-1821
- 全文大小：331K
- 年卷期：v.8,no.8(August 16, 2013)
- ISSN：1554-8937
文摘
Conotoxins have emerged as useful leads for the development of novel therapeutic analgesics. These peptides, isolated from marine molluscs of the genus Conus, have evolved exquisite selectivity for receptors and ion channels of excitable tissue. One such peptide, 伪-conotoxin Vc1.1, is a 16-mer possessing an interlocked disulfide framework. Despite its emergence as a potent analgesic lead, the molecular target and mechanism of action of Vc1.1 have not been elucidated to date. In this paper we describe the regioselective synthesis of dicarba analogues of Vc1.1 using olefin metathesis. The ability of these peptides to inhibit acetylcholine-evoked current at rat 伪9伪10 and 伪3尾4 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes has been assessed in addition to their ability to inhibit high voltage-activated (HVA) calcium channel current in isolated rat DRG neurons. Their solution structures were determined by NMR spectroscopy. Significantly, we have found that regioselective replacement of the native cystine framework with a dicarba bridge can be used to selectively tune the cyclic peptide鈥檚 innate biological activity for one receptor over another. The 2,8-dicarba Vc1.1 isomer retains activity at 纬-aminobutyric acid (GABAB) G protein-coupled receptors, whereas the isomeric 3,16-dicarba Vc1.1 peptide retains activity at the 伪9伪10 nAChR subtype. These singularly acting analogues will enable the elucidation of the biological target responsible for the peptide鈥檚 potent analgesic activity.