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