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Targeting of N-Type Calcium Channels via GABAB-Receptor Activation by α-Conotoxin Vc1.1 Variants Displaying Improved Analgesic Activity

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posted on 2024-11-16, 03:14 authored by Fengtao Cai, Ning Xu, Zhuguo Liu, Rong Ding, Shuo Yu, Mingxin Dong, Shuo Wang, Jintao Shen, Han Shen TaeHan Shen Tae, David AdamsDavid Adams, Xuerong Zhang, Qiuyun Dai
α-Conotoxins exhibiting analgesic activity, such as Vc1.1, have been shown to inhibit α9α10 nicotinic acetylcholine receptors (nAChRs) and GABAB-receptor (GABABR) coupled N-type (CaV2.2) calcium channels. Here, we report two Vc1.1 variants, Vc1.1[N9R] and benzoyl-Vc1.1[N9R], that selectively inhibit CaV2.2 channels via GABABR activation but exhibit reduced inhibitory activity at α9α10 and other neuronal nAChR subtypes compared with Vc1.1. Surprisingly, the analgesic activity of Vc1.1[N9R] and benzoyl-Vc1.1[N9R] was more potent than that of Vc1.1 when tested in partial sciatic nerve ligation injury and chronic constriction injury models. Vc1.1[N9R] and benzoyl-Vc1.1[N9R] exhibited either similar or tenfold higher activity of GABABR-mediated CaV2.2 inhibition but no activity at CaV2.2 alone; however, the mechanism of increased analgesic activity is unknown. The effects on analgesic activity and α9α10 nAChR of other Vc1.1 variations at position 9 and the N-terminus were also determined. Our findings provide new insights for designing potent inhibitors for GABABR-coupled N-type (CaV2.2) calcium channels.

Funding

Discovery and development of better pain treatments

National Health and Medical Research Council

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Citation

Cai, F., Xu, N., Liu, Z., Ding, R., Yu, S., Dong, M., Wang, S., Shen, J., Tae, H., Adams, D. J.., Zhang, X. & Dai, Q. (2018). Targeting of N-Type Calcium Channels via GABAB-Receptor Activation by α-Conotoxin Vc1.1 Variants Displaying Improved Analgesic Activity. Journal of Medicinal Chemistry, 61 (22), 10198-10205.

Journal title

Journal of Medicinal Chemistry

Volume

61

Issue

22

Pagination

10198-10205

Language

English

RIS ID

131879

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