Dicarba Analogues of 伪-Conotoxin RgIA. Structure, Stability, and Activity at Potential Pain Targets

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• 作者：Sandeep Chhabra ; Alessia Belgi ; Peter Bartels ; Bianca J. van Lierop ; Samuel D. Robinson ; Shiva N. Kompella ; Andrew Hung ; Brid P. Callaghan ; David J. Adams ; Andrea J. Robinson ; Raymond S. Norton
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：57
• 期：23
• 页码：9933-9944
• 全文大小：503K
• ISSN：1520-4804

文摘

伪-Conotoxin RgIA is both an antagonist of the 伪9伪10 nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor of high-voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain, but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with nonreducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets, and stability evaluated in human serum. [3,12]-Dicarba analogues retained inhibition of ACh-evoked currents at 伪9伪10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8]-dicarba RgIA analogues were effective in HEK293 cells stably expressing human Ca_v2.2 channels and transfected with human GABA_B receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors.