Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Apr 13;13(4):2030-45.
doi: 10.3390/md13042030.

Inhibition of N-type calcium channels by fluorophenoxyanilide derivatives

Ellen C Gleeson  1   2 , Janease E Graham  3   4 , Sandro Spiller  5 , Irina Vetter  6 , Richard J Lewis  7 , Peter J Duggan  8   9 , Kellie L Tuck  10
Affiliations

Inhibition of N-type calcium channels by fluorophenoxyanilide derivatives

Ellen C Gleeson et al. Mar Drugs. .

Abstract

A set of fluorophenoxyanilides, designed to be simplified analogues of previously reported ω-conotoxin GVIA mimetics, were prepared and tested for N-type calcium channel inhibition in a SH-SY5Y neuroblastoma FLIPR assay. N-type or Cav2.2 channel is a validated target for the treatment of refractory chronic pain. Despite being significantly less complex than the originally designed mimetics, up to a seven-fold improvement in activity was observed.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Chemical structure of Z160/NP11809 (1).
Figure 2
Figure 2
Structures of previously synthesised anthranilamide-based ω-conotoxin GVIA mimetics (2–4) [25,27].
Figure 3
Figure 3
Analogues 5a–c and 6a–c targeted in this study.
Scheme 1
Scheme 1
Synthesis of meta-(4-fluorophenoxy)aniline (10b). Reagents and conditions: (a) Cu(OAc)2, Et3N, air, 4 Å molecular sieves, dichloromethane (DCM), room temperature (RT), 24 h 83%; (b) Pd/C, NH2NH2·H2O, EtOH, RT, 4 h, 95%.
Scheme 2
Scheme 2
Synthesis of phenoxy anilides (5a–c and 6a–c). Reagents and conditions: (a) 4-(3-chloropropoxy)benzoic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl), 4-dimethylaminopyridine (DMAP), Et3N, DCM/tetrahydrofuran (THF), (11a) 47%, (11b) 81% or 4-(3-chloropropoxy)benzoyl chloride, THF, (11c) 70%; (b) NaN3, dimethyl sulfoxide (DMSO), 70 °C, (12a) 95%, (12b) 99%, (12c) 92%; (c) Pd/C, NH2NH2·H2O, MeOH, (5a–c) quant.; (d) 1H-pyrazole-1-carboximidine hydrochloride, N,N-diisopropylethylamine (DIPEA), dimethylformamide (DMF), (6a–c) quant.
See this image and copyright information in PMC

References

    1. Vink S., Alewood P.F. Targeting voltage-gated calcium channels: Developments in peptide and small-molecule inhibitors for the treatment of neuropathic pain. Br. J. Pharmacol. 2012;167:970–989. doi: 10.1111/j.1476-5381.2012.02082.x. - DOI - PMC - PubMed
    1. Altier C., Zamponi G.W. Targeting Ca2+ channels to treat pain: T-type versus N-type. Trends Pharmacol. Sci. 2004;25:465–470. doi: 10.1016/j.tips.2004.07.004. - DOI - PubMed
    1. Lee M.S. Chapter four—Recent progress in the discovery and development of N-type calcium channel modulators for the treatment of pain. In: Lawton G., Witty D.R., editors. Progress in Medicinal Chemistry. Volume 53. Elsevier; Oxford, UK: 2014. pp. 147–186. - PubMed
    1. Perret D., Luo Z.D. Targeting voltage-gated calcium channels for neuropathic pain management. NeuroRX. 2009;6:679–692. - PMC - PubMed
    1. Pope J.E., Deer T.R. Ziconotide: A clinical update and pharmacologic review. Exp. Opin. Pharmacother. 2013;14:957–966. doi: 10.1517/14656566.2013.784269. - DOI - PubMed

Publication types

MeSH terms

LinkOut - more resources