Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2

Shyamsunder R. Joolakanti; Justin R. Nickell; Venumadhav Janganati; Guangrong Zheng; Linda P. Dwoskin; Peter A. Crooks

doi:10.1016/j.bmcl.2016.03.119

Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [³H]dopamine uptake at the vesicular monoamine transporter-2

Shyamsunder R. Joolakanti, Justin R. Nickell, Venumadhav Janganati, Guangrong Zheng, Linda P. Dwoskin, Peter A. Crooks

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

3 Scopus citations

Abstract

A series of lobelane and GZ-793A analogues that incorporate aromatic 4-hydroxy and 4-(2-fluoroethoxy) substituents were synthesized and evaluated for inhibition of [³H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and the dopamine transporter (DAT), and [³H]serotonin uptake at the serotonin transporter (SERT). Most of these compounds exhibited potent inhibition of DA uptake at VMAT2 in the nanomolar range (K_i = 30-70 nM). The two most potent analogues, 7 and 14, both exhibited a K_i value of 31 nM for inhibition of VMAT2. The lobelane analogue 14, incorporating 4-(2-fluoroethoxy) and 4-hydroxy aromatic substituents, exhibited 96- and 335-fold greater selectivity for VMAT2 versus DAT and SERT, respectively, in comparison to lobelane. Thus, lobelane analogues bearing hydroxyl and fluoroethoxy moieties retain the high affinity for VMAT2 of the parent compound, while enhancing selectivity for VMAT2 versus the plasmalemma transporters.

Original language	English
Pages (from-to)	2422-2427
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2016.03.119
State	Published - May 1 2016

Bibliographical note

Publisher Copyright:
© 2016 Elsevier B.V. All rights reserved.

Funding

This research was supported by NIH U01 DA13519 , 5T32 DA022981 , TR000117 and NIH/COBRA P20 GM109005 grants, and an Arkansas Research Alliance (ARA) Scholar award.

Funders	Funder number
NIH/COBRA	P20 GM109005
National Institutes of Health (NIH)	TR000117, 5T32 DA022981
National Institute on Drug Abuse	U01DA013519
Arkansas Research Alliance

Keywords

4-Hydroxyphenyl lobelane analogues
Dopamine and serotonin transporter
Dopamine uptake
Fluorinated lobelane analogues
Vesicular monoamine transporter-2

ASJC Scopus subject areas

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

Access to Document

10.1016/j.bmcl.2016.03.119

Cite this

Joolakanti, S. R., Nickell, J. R., Janganati, V., Zheng, G., Dwoskin, L. P., & Crooks, P. A. (2016). Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [³H]dopamine uptake at the vesicular monoamine transporter-2. Bioorganic and Medicinal Chemistry Letters, 26(10), 2422-2427. https://doi.org/10.1016/j.bmcl.2016.03.119

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title = "Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2",

abstract = "A series of lobelane and GZ-793A analogues that incorporate aromatic 4-hydroxy and 4-(2-fluoroethoxy) substituents were synthesized and evaluated for inhibition of [3H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and the dopamine transporter (DAT), and [3H]serotonin uptake at the serotonin transporter (SERT). Most of these compounds exhibited potent inhibition of DA uptake at VMAT2 in the nanomolar range (Ki = 30-70 nM). The two most potent analogues, 7 and 14, both exhibited a Ki value of 31 nM for inhibition of VMAT2. The lobelane analogue 14, incorporating 4-(2-fluoroethoxy) and 4-hydroxy aromatic substituents, exhibited 96- and 335-fold greater selectivity for VMAT2 versus DAT and SERT, respectively, in comparison to lobelane. Thus, lobelane analogues bearing hydroxyl and fluoroethoxy moieties retain the high affinity for VMAT2 of the parent compound, while enhancing selectivity for VMAT2 versus the plasmalemma transporters.",

keywords = "4-Hydroxyphenyl lobelane analogues, Dopamine and serotonin transporter, Dopamine uptake, Fluorinated lobelane analogues, Vesicular monoamine transporter-2",

author = "Joolakanti, {Shyamsunder R.} and Nickell, {Justin R.} and Venumadhav Janganati and Guangrong Zheng and Dwoskin, {Linda P.} and Crooks, {Peter A.}",

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Joolakanti, SR, Nickell, JR, Janganati, V, Zheng, G, Dwoskin, LP & Crooks, PA 2016, 'Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [³H]dopamine uptake at the vesicular monoamine transporter-2', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 10, pp. 2422-2427. https://doi.org/10.1016/j.bmcl.2016.03.119

Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [³H]dopamine uptake at the vesicular monoamine transporter-2. / Joolakanti, Shyamsunder R.; Nickell, Justin R.; Janganati, Venumadhav et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 10, 01.05.2016, p. 2422-2427.

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

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AU - Zheng, Guangrong

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