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.
|Number of pages||6|
|Journal||Bioorganic and Medicinal Chemistry Letters|
|State||Published - Dec 15 2017|
Bibliographical noteFunding Information:
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.
© 2017 Elsevier Ltd
- Dopamine uptake
- Fluoroethoxy piperidine and piperazine analogs
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry