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

Producción científica: Article › revisión exhaustiva

3 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	5467-5472
Número de páginas	6
Publicación	Bioorganic and Medicinal Chemistry Letters
Volumen	27
N.º	24
DOI	https://doi.org/10.1016/j.bmcl.2017.10.039
Estado	Published - dic 15 2017

Nota bibliográfica

Publisher Copyright:
© 2017 Elsevier Ltd

Financiación

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.

Financiadores	Número del financiador
National Institutes of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)	UL1TR000117
National Center for Advancing Translational Sciences (NCATS)
Arkansas Research Alliance

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.2017.10.039

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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.\}",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",

year = "2017",

month = dec,

day = "15",

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

language = "English",

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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, n.º 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.
En: Bioorganic and Medicinal Chemistry Letters, Vol. 27, N.º 24, 15.12.2017, p. 5467-5472.

Producción científica: Article › revisión exhaustiva

TY - JOUR

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

Y1 - 2017/12/15

N2 - 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.

AB - 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.

KW - Dopamine uptake

KW - Fluoroethoxy piperidine and piperazine analogs

KW - Lobelane

KW - VMAT2

KW - hERG

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