Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2

Emily R. Hankosky; Shyam R. Joolakanti; Justin R. Nickell; Venumadhav Janganati; Linda P. Dwoskin; Peter A. Crooks

doi:10.1016/j.bmcl.2017.10.039

Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [³H]dopamine uptake at the vesicular monoamine transporter-2

Emily R. Hankosky, Shyam R. Joolakanti, Justin R. Nickell, Venumadhav Janganati, Linda P. Dwoskin, Peter A. Crooks

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

3 Scopus citations

Abstract

A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [³H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [³H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [³H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [³H]DA uptake at VMAT2, Ki changes in the nanomolar range (K_i = 0.014–0.073 µM). Compound 15d exhibited the highest affinity (K_i = 0.014 µM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (K_i = 0.073 µM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2.

Original language	English
Pages (from-to)	5467-5472
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	27
Issue number	24
DOIs	https://doi.org/10.1016/j.bmcl.2017.10.039
State	Published - Dec 15 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Ltd

Funding

This research was supported by DA013519 , TR000117 , TR001998 and GM109005 NIH grants, and an Arkansas Research Alliance (ARA) Scholar award. The University of Kentucky holds patents on the novel compounds described herein. A potential royalty stream to LPD and PAC may occur consistent with University of Kentucky policy.

Funders	Funder number
National Institutes of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)	UL1TR000117
National Center for Advancing Translational Sciences (NCATS)
Arkansas Research Alliance

Keywords

Dopamine uptake
Fluoroethoxy piperidine and piperazine analogs
Lobelane
VMAT2
hERG

ASJC Scopus subject areas

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

Access to Document

10.1016/j.bmcl.2017.10.039

Cite this

Hankosky, E. R., Joolakanti, S. R., Nickell, J. R., Janganati, V., Dwoskin, L. P., & Crooks, P. A. (2017). Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [³H]dopamine uptake at the vesicular monoamine transporter-2. Bioorganic and Medicinal Chemistry Letters, 27(24), 5467-5472. https://doi.org/10.1016/j.bmcl.2017.10.039

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title = "Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2",

abstract = "A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [3H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [3H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [3H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [3H]DA uptake at VMAT2, Ki changes in the nanomolar range (Ki = 0.014–0.073 µM). Compound 15d exhibited the highest affinity (Ki = 0.014 µM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (Ki = 0.073 µM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2.",

keywords = "Dopamine uptake, Fluoroethoxy piperidine and piperazine analogs, Lobelane, VMAT2, hERG",

author = "Hankosky, \{Emily R.\} and Joolakanti, \{Shyam R.\} and Nickell, \{Justin R.\} and Venumadhav Janganati and Dwoskin, \{Linda P.\} and Crooks, \{Peter A.\}",

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year = "2017",

month = dec,

day = "15",

doi = "10.1016/j.bmcl.2017.10.039",

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Hankosky, ER, Joolakanti, SR, Nickell, JR, Janganati, V, Dwoskin, LP & Crooks, PA 2017, 'Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [³H]dopamine uptake at the vesicular monoamine transporter-2', Bioorganic and Medicinal Chemistry Letters, vol. 27, no. 24, pp. 5467-5472. https://doi.org/10.1016/j.bmcl.2017.10.039

Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [³H]dopamine uptake at the vesicular monoamine transporter-2. / Hankosky, Emily R.; Joolakanti, Shyam R.; Nickell, Justin R. et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 27, No. 24, 15.12.2017, p. 5467-5472.

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

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T1 - Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives

T2 - Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2

AU - Hankosky, Emily R.

AU - Joolakanti, Shyam R.

AU - Nickell, Justin R.

AU - Janganati, Venumadhav

AU - Dwoskin, Linda P.

AU - Crooks, Peter A.

PY - 2017/12/15

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KW - Dopamine uptake

KW - Fluoroethoxy piperidine and piperazine analogs

KW - Lobelane

KW - VMAT2

KW - hERG

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