Structural analogs of huperzine A improve survival in guinea pigs exposed to soman

Hendra Gunosewoyo; Suresh K. Tipparaju; Marco Pieroni; Ying Wang; Bhupendra P. Doctor; Madhusoodana P. Nambiar; Alan P. Kozikowski

doi:10.1016/j.bmcl.2012.11.083

Structural analogs of huperzine A improve survival in guinea pigs exposed to soman

Hendra Gunosewoyo, Suresh K. Tipparaju, Marco Pieroni, Ying Wang, Bhupendra P. Doctor, Madhusoodana P. Nambiar, Alan P. Kozikowski

School of Medicine

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

7 Scopus citations

Abstract

Chemical warfare nerve agents such as soman exert their toxic effects through an irreversible inhibition of acetylcholinesterase (AChE) and subsequently glutamatergic function, leading to uncontrolled seizures. The natural alkaloid (-)-huperzine A is a potent inhibitor of AChE and has been demonstrated to exert neuroprotection at an appropriate dose. It is hypothesized that analogs of both (+)- and (-)-huperzine A with an improved ability to interact with NMDA receptors together with reduced AChE inhibition will exhibit more effective neuroprotection against nerve agents. In this manuscript, the tested huperzine A analogs 2 and 3 were demonstrated to improve survival of guinea pigs exposed to soman at either 1.2 or 2 × LD₅₀.

Original language	English (US)
Pages (from-to)	1544-1547
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	5
DOIs	https://doi.org/10.1016/j.bmcl.2012.11.083
State	Published - Mar 1 2013

Keywords

Acetylcholinesterase
Huperzine A analogs
Nerve agent
Neuroprotection
Soman

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.2012.11.083

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title = "Structural analogs of huperzine A improve survival in guinea pigs exposed to soman",

abstract = "Chemical warfare nerve agents such as soman exert their toxic effects through an irreversible inhibition of acetylcholinesterase (AChE) and subsequently glutamatergic function, leading to uncontrolled seizures. The natural alkaloid (-)-huperzine A is a potent inhibitor of AChE and has been demonstrated to exert neuroprotection at an appropriate dose. It is hypothesized that analogs of both (+)- and (-)-huperzine A with an improved ability to interact with NMDA receptors together with reduced AChE inhibition will exhibit more effective neuroprotection against nerve agents. In this manuscript, the tested huperzine A analogs 2 and 3 were demonstrated to improve survival of guinea pigs exposed to soman at either 1.2 or 2 × LD50.",

keywords = "Acetylcholinesterase, Huperzine A analogs, Nerve agent, Neuroprotection, Soman",

author = "Hendra Gunosewoyo and Tipparaju, {Suresh K.} and Marco Pieroni and Ying Wang and Doctor, {Bhupendra P.} and Nambiar, {Madhusoodana P.} and Kozikowski, {Alan P.}",

note = "Funding Information: This work was supported by the US Army Medical Research and Material Command (Contract number W81XWH-08-1-0201 ). H.G. would like to thank Dr. Werner T{\"u}ckmantel for his critical proofreading of the manuscript. Copyright: Copyright 2014 Elsevier B.V., All rights reserved.",

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doi = "10.1016/j.bmcl.2012.11.083",

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AU - Gunosewoyo, Hendra

AU - Tipparaju, Suresh K.

AU - Pieroni, Marco

AU - Wang, Ying

AU - Doctor, Bhupendra P.

AU - Nambiar, Madhusoodana P.

AU - Kozikowski, Alan P.

N1 - Funding Information: This work was supported by the US Army Medical Research and Material Command (Contract number W81XWH-08-1-0201 ). H.G. would like to thank Dr. Werner Tückmantel for his critical proofreading of the manuscript. Copyright: Copyright 2014 Elsevier B.V., All rights reserved.

PY - 2013/3/1

Y1 - 2013/3/1

N2 - Chemical warfare nerve agents such as soman exert their toxic effects through an irreversible inhibition of acetylcholinesterase (AChE) and subsequently glutamatergic function, leading to uncontrolled seizures. The natural alkaloid (-)-huperzine A is a potent inhibitor of AChE and has been demonstrated to exert neuroprotection at an appropriate dose. It is hypothesized that analogs of both (+)- and (-)-huperzine A with an improved ability to interact with NMDA receptors together with reduced AChE inhibition will exhibit more effective neuroprotection against nerve agents. In this manuscript, the tested huperzine A analogs 2 and 3 were demonstrated to improve survival of guinea pigs exposed to soman at either 1.2 or 2 × LD50.

AB - Chemical warfare nerve agents such as soman exert their toxic effects through an irreversible inhibition of acetylcholinesterase (AChE) and subsequently glutamatergic function, leading to uncontrolled seizures. The natural alkaloid (-)-huperzine A is a potent inhibitor of AChE and has been demonstrated to exert neuroprotection at an appropriate dose. It is hypothesized that analogs of both (+)- and (-)-huperzine A with an improved ability to interact with NMDA receptors together with reduced AChE inhibition will exhibit more effective neuroprotection against nerve agents. In this manuscript, the tested huperzine A analogs 2 and 3 were demonstrated to improve survival of guinea pigs exposed to soman at either 1.2 or 2 × LD50.

KW - Acetylcholinesterase

KW - Huperzine A analogs

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KW - Neuroprotection

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Structural analogs of huperzine A improve survival in guinea pigs exposed to soman

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Keywords

ASJC Scopus subject areas

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