Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants

Jia Zhou; Thomas Kläß; Kenneth M. Johnson; Kelly M. Giberson; Alan P. Kozikowski

doi:10.1016/j.bmcl.2005.03.083

Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants

Jia Zhou
, Thomas Kläß
, Kenneth M. Johnson
, Kelly M. Giberson
, Alan P. Kozikowski

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

5 Scopus citations

Abstract

To further explore the structure-activity relationships of conformationally constrained tropanes, a number of new biaryl and arylacetylene analogs were designed and synthesized. Some of these compounds such as 3a-b, 3d, 3f-h, 5b, and 7g were found to be highly potent and selective or mixed norepinephrine transporter (NET) inhibitors with K_i values of 0.8-9.4 nM. Moreover, all of these compounds display weak to extremely weak muscarinic receptor binding affinity, indicating that as potential antidepressants, they may overcome certain side effects that are of concern with other antidepressants, which are thought to be mediated by their anticholinergic properties.

Original language	English (US)
Pages (from-to)	2461-2465
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	15
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2005.03.083
State	Published - May 16 2005
Externally published	Yes

Keywords

Antidepressants
Biaryl and arylacetylene ligands
Conformationally constrained tropanes
Muscarinic receptor affinity
NET inhibitors

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.2005.03.083

Cite this

Zhou, J., Kläß, T., Johnson, K. M., Giberson, K. M., & Kozikowski, A. P. (2005). Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants. Bioorganic and Medicinal Chemistry Letters, 15(10), 2461-2465. https://doi.org/10.1016/j.bmcl.2005.03.083

Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants. / Zhou, Jia; Kläß, Thomas; Johnson, Kenneth M. et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 15, No. 10, 16.05.2005, p. 2461-2465.

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

Zhou, J, Kläß, T, Johnson, KM, Giberson, KM & Kozikowski, AP 2005, 'Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants', Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 10, pp. 2461-2465. https://doi.org/10.1016/j.bmcl.2005.03.083

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title = "Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants",

abstract = "To further explore the structure-activity relationships of conformationally constrained tropanes, a number of new biaryl and arylacetylene analogs were designed and synthesized. Some of these compounds such as 3a-b, 3d, 3f-h, 5b, and 7g were found to be highly potent and selective or mixed norepinephrine transporter (NET) inhibitors with Ki values of 0.8-9.4 nM. Moreover, all of these compounds display weak to extremely weak muscarinic receptor binding affinity, indicating that as potential antidepressants, they may overcome certain side effects that are of concern with other antidepressants, which are thought to be mediated by their anticholinergic properties.",

keywords = "Antidepressants, Biaryl and arylacetylene ligands, Conformationally constrained tropanes, Muscarinic receptor affinity, NET inhibitors",

author = "Jia Zhou and Thomas Kl{\"a}{\ss} and Johnson, \{Kenneth M.\} and Giberson, \{Kelly M.\} and Kozikowski, \{Alan P.\}",

note = "Funding Information: This work was supported by an STTR grant from NIH/NIMH (1R41MH070083-01) and grants from NIH/NIDA (DA10458, DA11548). The authors also thank Dr. Werner Tueckmantel and Mr. Hans F. Roth of Acenta Discovery, Inc. for helpful discussions. ",

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AU - Giberson, Kelly M.

AU - Kozikowski, Alan P.

N1 - Funding Information: This work was supported by an STTR grant from NIH/NIMH (1R41MH070083-01) and grants from NIH/NIDA (DA10458, DA11548). The authors also thank Dr. Werner Tueckmantel and Mr. Hans F. Roth of Acenta Discovery, Inc. for helpful discussions.

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AB - To further explore the structure-activity relationships of conformationally constrained tropanes, a number of new biaryl and arylacetylene analogs were designed and synthesized. Some of these compounds such as 3a-b, 3d, 3f-h, 5b, and 7g were found to be highly potent and selective or mixed norepinephrine transporter (NET) inhibitors with Ki values of 0.8-9.4 nM. Moreover, all of these compounds display weak to extremely weak muscarinic receptor binding affinity, indicating that as potential antidepressants, they may overcome certain side effects that are of concern with other antidepressants, which are thought to be mediated by their anticholinergic properties.

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KW - Biaryl and arylacetylene ligands

KW - Conformationally constrained tropanes

KW - Muscarinic receptor affinity

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Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants

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Keywords

ASJC Scopus subject areas

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