Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors

Hassan Pajouhesh; Zhong Ping Feng; Yanbing Ding; Lingyun Zhang; Hossein Pajouhesh; Jerrie Lynn Morrison; Francesco Belardetti; Elizabeth Tringham; Eric Simonson; Todd W. Vanderah; Frank Porreca; Gerald W. Zamponi; Lester A. Mitscher; Terrance P. Snutch

doi:10.1016/j.bmcl.2010.01.008

Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors

Hassan Pajouhesh, Zhong Ping Feng, Yanbing Ding, Lingyun Zhang, Hossein Pajouhesh, Jerrie Lynn Morrison, Francesco Belardetti, Elizabeth Tringham, Eric Simonson, Todd W. Vanderah, Frank Porreca, Gerald W. Zamponi, Lester A. Mitscher, Terrance P. Snutch

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

Abstract

A novel series of compounds derived from the previously reported N-type calcium channel blocker NP118809 (1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one) is described. Extensive SAR studies resulted in compounds with IC₅₀ values in the range of 10-150 nM and selectivity over the L-type channels up to nearly 1200-fold. Orally administered compounds 5 and 21 exhibited both anti-allodynic and anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain.

Original language	English (US)
Pages (from-to)	1378-1383
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	4
DOIs	https://doi.org/10.1016/j.bmcl.2010.01.008
State	Published - Feb 15 2010

Keywords

Calcium channel
Diphenylpiperazine
L-type
N-type
Pain

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2010.01.008

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Pajouhesh, H., Feng, Z. P., Ding, Y., Zhang, L., Pajouhesh, H., Morrison, J. L., Belardetti, F., Tringham, E., Simonson, E., Vanderah, T. W., Porreca, F., Zamponi, G. W., Mitscher, L. A., & Snutch, T. P. (2010). Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors. Bioorganic and Medicinal Chemistry Letters, 20(4), 1378-1383. https://doi.org/10.1016/j.bmcl.2010.01.008

Pajouhesh, H, Feng, ZP, Ding, Y, Zhang, L, Pajouhesh, H, Morrison, JL, Belardetti, F, Tringham, E, Simonson, E, Vanderah, TW , Porreca, F, Zamponi, GW, Mitscher, LA & Snutch, TP 2010, 'Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 4, pp. 1378-1383. https://doi.org/10.1016/j.bmcl.2010.01.008

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abstract = "A novel series of compounds derived from the previously reported N-type calcium channel blocker NP118809 (1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one) is described. Extensive SAR studies resulted in compounds with IC50 values in the range of 10-150 nM and selectivity over the L-type channels up to nearly 1200-fold. Orally administered compounds 5 and 21 exhibited both anti-allodynic and anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain.",

keywords = "Calcium channel, Diphenylpiperazine, L-type, N-type, Pain",

author = "Hassan Pajouhesh and Feng, {Zhong Ping} and Yanbing Ding and Lingyun Zhang and Hossein Pajouhesh and Morrison, {Jerrie Lynn} and Francesco Belardetti and Elizabeth Tringham and Eric Simonson and Vanderah, {Todd W.} and Frank Porreca and Zamponi, {Gerald W.} and Mitscher, {Lester A.} and Snutch, {Terrance P.}",

note = "Funding Information: We thank Molly Fee-Maki for helpful discussions concerning the rat PK data. Work in the laboratories of T.P.S. and G.W.Z. is supported by the Canadian Institutes of Health Research. T.P.S. a Canada Research Chair in Biotechnology and Genomics-Neurobiology. G.W.Z. is a Scientist of the Alberta Heritage Foundation for Medical Research and is also supported by a Canada Research Chair in Molecular Neurobiology.",

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language = "English (US)",

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AU - Pajouhesh, Hassan

AU - Feng, Zhong Ping

AU - Ding, Yanbing

AU - Zhang, Lingyun

AU - Pajouhesh, Hossein

AU - Morrison, Jerrie Lynn

AU - Belardetti, Francesco

AU - Tringham, Elizabeth

AU - Simonson, Eric

AU - Vanderah, Todd W.

AU - Porreca, Frank

AU - Zamponi, Gerald W.

AU - Mitscher, Lester A.

AU - Snutch, Terrance P.

N1 - Funding Information: We thank Molly Fee-Maki for helpful discussions concerning the rat PK data. Work in the laboratories of T.P.S. and G.W.Z. is supported by the Canadian Institutes of Health Research. T.P.S. a Canada Research Chair in Biotechnology and Genomics-Neurobiology. G.W.Z. is a Scientist of the Alberta Heritage Foundation for Medical Research and is also supported by a Canada Research Chair in Molecular Neurobiology.

PY - 2010/2/15

Y1 - 2010/2/15

N2 - A novel series of compounds derived from the previously reported N-type calcium channel blocker NP118809 (1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one) is described. Extensive SAR studies resulted in compounds with IC50 values in the range of 10-150 nM and selectivity over the L-type channels up to nearly 1200-fold. Orally administered compounds 5 and 21 exhibited both anti-allodynic and anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain.

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KW - Diphenylpiperazine

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KW - N-type

KW - Pain

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Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors

Abstract

Keywords

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