Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2 |
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Authors: | Emily R Hankosky Shyam R Joolakanti Justin R Nickell Venumadhav Janganati Linda P Dwoskin Peter A Crooks |
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Institution: | 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA;2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA |
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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. |
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Keywords: | Lobelane Fluoroethoxy piperidine and piperazine analogs VMAT2 Dopamine uptake hERG |
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