Skip to main content
placeholder image

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

Journal Article


Abstract


  • 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.

UOW Authors


  •   Cai, Fengtao (external author)
  •   Xu, Ning (external author)
  •   Liu, Zhuguo (external author)
  •   Ding, Rong (external author)
  •   Yu, Shuo (external author)
  •   Dong, Mingxin (external author)
  •   Wang, Shuo (external author)
  •   Shen, Jintao (external author)
  •   Tae, Han Shen
  •   Adams, David
  •   Zhang, Xuerong (external author)
  •   Dai, Qiuyun (external author)

Publication Date


  • 2018

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.

Scopus Eid


  • 2-s2.0-85056555694

Number Of Pages


  • 7

Start Page


  • 10198

End Page


  • 10205

Volume


  • 61

Issue


  • 22

Place Of Publication


  • United States

Abstract


  • 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.

UOW Authors


  •   Cai, Fengtao (external author)
  •   Xu, Ning (external author)
  •   Liu, Zhuguo (external author)
  •   Ding, Rong (external author)
  •   Yu, Shuo (external author)
  •   Dong, Mingxin (external author)
  •   Wang, Shuo (external author)
  •   Shen, Jintao (external author)
  •   Tae, Han Shen
  •   Adams, David
  •   Zhang, Xuerong (external author)
  •   Dai, Qiuyun (external author)

Publication Date


  • 2018

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.

Scopus Eid


  • 2-s2.0-85056555694

Number Of Pages


  • 7

Start Page


  • 10198

End Page


  • 10205

Volume


  • 61

Issue


  • 22

Place Of Publication


  • United States