Fluoroethoxy-1,4-diphenethylpiperidine and Piperazine Derivatives: Potent and Selective Inhibitors of [³H]Dopamine Uptake at the Vesicular Monoamine Transporter-2

Authors

Emily R. Hankosky, University of KentuckyFollow
Shyam R. Joolakanti, University of Arkansas for Medical Sciences
Justin R. Nickell, University of KentuckyFollow
Venumadhav Janganati, University of Arkansas for Medical Sciences
Linda P. Dwoskin, University of KentuckyFollow
Peter A. Crooks, University of Arkansas for Medical Sciences

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, with Ki values 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.

Document Type

Article

Publication Date

12-15-2017

Notes/Citation Information

Published in Bioorganic & Medicinal Chemistry Letters, v. 27, issue 24, p. 5467-5472.

© 2017 Elsevier Ltd. All rights reserved.

This manuscript version is made available under the CC‐BY‐NC‐ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/.

The document available for download is the author's post-peer-review final draft of the article.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.bmcl.2017.10.039

Funding Information

This research was supported by DA013519, TR000117, TR001998 and GM109005 NIH grants, and an Arkansas Research Alliance (ARA) Scholar award.

Related Content

Refer to Web version on PubMed Central for supplementary material.

Repository Citation

Hankosky, Emily R.; Joolakanti, Shyam R.; Nickell, Justin R.; Janganati, Venumadhav; Dwoskin, Linda P.; and Crooks, Peter A., "Fluoroethoxy-1,4-diphenethylpiperidine and Piperazine Derivatives: Potent and Selective Inhibitors of [³H]Dopamine Uptake at the Vesicular Monoamine Transporter-2" (2017). Pharmaceutical Sciences Faculty Publications. 123.
https://uknowledge.uky.edu/ps_facpub/123