- 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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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.
- Hankosky, Emily R.,Joolakanti, Shyam R.,Nickell, Justin R.,Janganati, Venumadhav,Dwoskin, Linda P.,Crooks, Peter A.
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p. 5467 - 5472
(2017/11/21)
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- 1,4-Diphenalkylpiperidines: A new scaffold for the design of potent inhibitors of the vesicular monoamine transporter-2
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A series of 1,4-diphenalkylpiperidine analogs were synthesized and evaluated for their affinity and inhibitory potency at the [3H]dihydrotetrabenazine (DTBZ) binding site and [3H]dopamine (DA) uptake site on the vesicular monoamine transporter-2 (VMAT2). Results revealed that translocation of the phenethyl side chains of lobelane from C2 and C6 to C1 and C4 around the central piperidine ring slightly reduces affinity and inhibitory potency at VMAT2 with respect to lobelane. However, methoxy and fluoro-substitution of either phenyl ring of these 1,4-diphenethyl analogs afforded VMAT2 inhibition comparable or higher (5-fold) affinity at the DTBZ binding and DA uptake sites relative to lobelane, whereas replacement of the 4-phenethyl moiety in these analogs with a 4-phenmethyl moiety markedly reduced affinity for the DTBZ binding and DA uptake sites by 3- and 5-fold, respectively. Among the twenty five 1,4-diphenethylpiperidine analogs evaluated, compounds containing a 4-(2-methoxyphenethyl) moiety exhibited the most potent inhibition of DTBZ binding and vesicular DA uptake. From this subgroup, analogs 8h, 8j and 8m exhibited Ki values of 9.3 nM, 13 nM and 13 nM, respectively, for inhibition of [3H]DA uptake by VMAT2, and represent some of the most potent inhibitors of VMAT2 function reported thus far.
- Nickell, Justin R.,Culver, John P.,Janganati, Venumadhav,Zheng, Guangrong,Dwoskin, Linda P.,Crooks, Peter A.
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supporting information
p. 2997 - 3000
(2016/06/13)
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- 1,4-DISUBSTITUTED PIPERIDINES, 1,4-DISUBSTITUTED PIPERAZINES, 1,4-DISUBSTITUTED DIAZEPANES, AND 1,3-DISUBSTITUTED PYRROLIDINE COMPOUNDS
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The present invention is directed to 1,4-disubstituted piperidines, 1,4-disubstituted piperazines, 1,4-disubstituted diazepanes, and 1,3-disubstituted pyrrolidine compounds and their use.
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Page/Page column 10-11
(2014/09/29)
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- New functionalised silicas for highly selective cation exchange SPE purification in medicinal chemistry
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Functionalised silicas 2 and 3 are effective for the cation exchange SPE purification of basic molecules containing acid-sensitive functionalities, the selective separations of mixtures of basic compounds and accelerated reaction work-ups/product isolatio
- Brown, Jane,Chighine, Alessandra,Colucci, Marie A.,Galaffu, Nicola,Hirst, Simon C.,Seymour, Helen M.,Shiers, Jason J.,Wilkes, Robin D.,Williams, Jonathan G.,Wilson, John R.H.
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p. 4968 - 4971
(2008/09/21)
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- Lobelane analogues as novel ligands for the vesicular monoamine transporter-2
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A series of lobelane analogues has been synthesized and their structure-activity relationships at the vesicular monoamine transporter-2 (VMAT2) have been evaluated. The most potent analogues in this series were the cis-2,6-piperidino analogues, 25b, 27b, 28b, and 30b, with Ki values ranging from 430 to 580 nM.
- Zheng, Guangrong,Dwoskin, Linda P.,Deaciuc, Agripina G.,Zhu, Jun,Jones, Marlon D.,Crooks, Peter A.
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p. 3899 - 3909
(2007/10/03)
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- Saturated heterocyclic carboxamide derivatives
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A saturated heterocyclic carboxamide derivative of the following general formula (I) and salts thereof which have platelet activating factor (PAF) antagonizing activity. STR1
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