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

Producción científica: Article › revisión exhaustiva

16 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	3874-3880
Número de páginas	7
Publicación	Bioorganic and Medicinal Chemistry Letters
Volumen	15
N.º	17
DOI	https://doi.org/10.1016/j.bmcl.2005.05.118
Estado	Published - sept 1 2005

Nota bibliográfica

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.

Financiación

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.

Financiadores	Número del financiador
National Institutes of Health (NIH)	GM57481-01A2, DA-05274
National Institute on Drug Abuse	U19DA017548

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.2005.05.118

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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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AU - Dwoskin, Linda P.

AU - Crooks, Peter A.

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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.

KW - Alzheimer's disease

KW - Oocyte

KW - Schizophrenia

KW - Voltage clamp

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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

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

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