The characterization of a novel rigid nicotine analog with α7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion

Roger L. Papke; Guangrong Zheng; Nicole A. Horenstein; Linda P. Dwoskin; Peter A. Crooks

doi:10.1016/j.bmcl.2005.05.118

The characterization of a novel rigid nicotine analog with α7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion

Roger L. Papke
, Guangrong Zheng
, Nicole A. Horenstein
, Linda P. Dwoskin
, Peter A. Crooks

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

16 Scopus citations

Abstract

The α7 nAChR subtype is of particular interest as a potential therapeutic target since it has been implicated as a mediator of both cognitive and neuroprotective activity. The rigid nicotine analog ACME and the N-cyanoborane conjugate ACME-B are selective partial agonists of rat α7 receptors expressed in Xenopus oocytes, with no significant activation of either α3β4 or α4β2 receptors. ACME-B is both more potent and efficacious than ACME. The efficacies of ACME-B and ACME are approximately 26% and 10% of the efficacy of ACh, respectively. Similar N-conjugation of S(-)nicotine with cyanoborane decreased efficacy for α3β4 and α4β2 receptors, as well as for α7 nAChR. Structural comparison of ACME with the benzylidene anabaseines, another class of previously identified α7-selective agonists, suggests that they share a similar structural motif that may be applicable to other α7-selective agonists.

Original language	English
Pages (from-to)	3874-3880
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	15
Issue number	17
DOIs	https://doi.org/10.1016/j.bmcl.2005.05.118
State	Published - Sep 1 2005

Bibliographical note

Funding Information:
This work was supported by NIH Grants GM57481-01A2 and DA-05274, DA-017548. We thank Clare Stokes for technical assistance. We are very grateful to Axon Instruments/Molecular Devices for the use of an OpusXpress 6000A and pClamp9. We particularly thank Dr. Cathy Smith-Maxwell for her support and help with OpusXpress.

Funding

This work was supported by NIH Grants GM57481-01A2 and DA-05274, DA-017548. We thank Clare Stokes for technical assistance. We are very grateful to Axon Instruments/Molecular Devices for the use of an OpusXpress 6000A and pClamp9. We particularly thank Dr. Cathy Smith-Maxwell for her support and help with OpusXpress.

Funders	Funder number
National Institutes of Health (NIH)	GM57481-01A2, DA-05274
National Institute on Drug Abuse	U19DA017548

Keywords

Alzheimer's disease
Oocyte
Schizophrenia
Voltage clamp

ASJC Scopus subject areas

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

Access to Document

10.1016/j.bmcl.2005.05.118

Cite this

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title = "The characterization of a novel rigid nicotine analog with α7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion",

abstract = "The α7 nAChR subtype is of particular interest as a potential therapeutic target since it has been implicated as a mediator of both cognitive and neuroprotective activity. The rigid nicotine analog ACME and the N-cyanoborane conjugate ACME-B are selective partial agonists of rat α7 receptors expressed in Xenopus oocytes, with no significant activation of either α3β4 or α4β2 receptors. ACME-B is both more potent and efficacious than ACME. The efficacies of ACME-B and ACME are approximately 26\% and 10\% of the efficacy of ACh, respectively. Similar N-conjugation of S(-)nicotine with cyanoborane decreased efficacy for α3β4 and α4β2 receptors, as well as for α7 nAChR. Structural comparison of ACME with the benzylidene anabaseines, another class of previously identified α7-selective agonists, suggests that they share a similar structural motif that may be applicable to other α7-selective agonists.",

keywords = "Alzheimer's disease, Oocyte, Schizophrenia, Voltage clamp",

author = "Papke, \{Roger L.\} and Guangrong Zheng and Horenstein, \{Nicole A.\} and Dwoskin, \{Linda P.\} and Crooks, \{Peter A.\}",

note = "Funding Information: This work was supported by NIH Grants GM57481-01A2 and DA-05274, DA-017548. We thank Clare Stokes for technical assistance. We are very grateful to Axon Instruments/Molecular Devices for the use of an OpusXpress 6000A and pClamp9. We particularly thank Dr. Cathy Smith-Maxwell for her support and help with OpusXpress. ",

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The characterization of a novel rigid nicotine analog with α7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion. / Papke, Roger L.; Zheng, Guangrong; Horenstein, Nicole A. et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 15, No. 17, 01.09.2005, p. 3874-3880.

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

TY - JOUR

T1 - The characterization of a novel rigid nicotine analog with α7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion

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AU - Zheng, Guangrong

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AU - Dwoskin, Linda P.

AU - Crooks, Peter A.

N1 - Funding Information: This work was supported by NIH Grants GM57481-01A2 and DA-05274, DA-017548. We thank Clare Stokes for technical assistance. We are very grateful to Axon Instruments/Molecular Devices for the use of an OpusXpress 6000A and pClamp9. We particularly thank Dr. Cathy Smith-Maxwell for her support and help with OpusXpress.

PY - 2005/9/1

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N2 - The α7 nAChR subtype is of particular interest as a potential therapeutic target since it has been implicated as a mediator of both cognitive and neuroprotective activity. The rigid nicotine analog ACME and the N-cyanoborane conjugate ACME-B are selective partial agonists of rat α7 receptors expressed in Xenopus oocytes, with no significant activation of either α3β4 or α4β2 receptors. ACME-B is both more potent and efficacious than ACME. The efficacies of ACME-B and ACME are approximately 26% and 10% of the efficacy of ACh, respectively. Similar N-conjugation of S(-)nicotine with cyanoborane decreased efficacy for α3β4 and α4β2 receptors, as well as for α7 nAChR. Structural comparison of ACME with the benzylidene anabaseines, another class of previously identified α7-selective agonists, suggests that they share a similar structural motif that may be applicable to other α7-selective agonists.

AB - The α7 nAChR subtype is of particular interest as a potential therapeutic target since it has been implicated as a mediator of both cognitive and neuroprotective activity. The rigid nicotine analog ACME and the N-cyanoborane conjugate ACME-B are selective partial agonists of rat α7 receptors expressed in Xenopus oocytes, with no significant activation of either α3β4 or α4β2 receptors. ACME-B is both more potent and efficacious than ACME. The efficacies of ACME-B and ACME are approximately 26% and 10% of the efficacy of ACh, respectively. Similar N-conjugation of S(-)nicotine with cyanoborane decreased efficacy for α3β4 and α4β2 receptors, as well as for α7 nAChR. Structural comparison of ACME with the benzylidene anabaseines, another class of previously identified α7-selective agonists, suggests that they share a similar structural motif that may be applicable to other α7-selective agonists.

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KW - Oocyte

KW - Schizophrenia

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The characterization of a novel rigid nicotine analog with α7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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