TY - JOUR
T1 - Syntheses of 3-carbomethoxy-4-(aryl)piperidines and in vitro and in vivo pharmacological evaluation
T2 - Identification of inhibitors of the human dopamine transporter
AU - Feng, Xianqi
AU - Fandrick, Keith
AU - Johnson, Robert
AU - Janowsky, Aaron
AU - Cashman, John R.
N1 - Funding Information:
We acknowledge the generous gifts of authentic cocaine and cocaine metabolites provided from the Drug Supply Program of the National Institute on Drug Abuse. We thank Dr. Jonathan Katz of the Intramural Research Program of the National Institute on Drug Abuse (Baltimore, MD, USA) for performing the in vivo studies. The financial support of the National Institute on Drug Abuse, National Institutes of Health, Grant DA08531 is gratefully acknowledged.
PY - 2003/3
Y1 - 2003/3
N2 - A series of 3-carbomethoxy-4-(aryl-substituted)piperidines with various aryl groups were synthesized and examined for binding and reuptake inhibition at the human dopamine transporter, the human serotonin transporter, and the human norepinephrine transporter. The binding potency and reuptake inhibition efficacy was compared with that of (-)-cocaine to determine the significance of removing the two-carbon bridge of the cocaine nucleus on the inhibition of transporter binding and reuptake. Of the transporters examined, the substituted piperidines were relatively selective for the human dopamine transporter. In all cases examined, the cis-diastereomer of the 3-carbomethoxy-4-(aryl-substituted)piperidine was observed to be a more potent inhibitor of the human dopamine transporter than the trans diastereomer. Based on the Ki (binding) and IC50 (reuptake inhibition) values obtained, the most potent inhibitor of the series was cis-3-carbomethoxy-4-(4′-chlorophenyl)piperidine, and this compound suppressed spontaneous- and cocaine-induced stimulation in non-habituated male Swiss-Webster mice. The conclusion is that substantial portions of the cocaine structure can be dissected away to provide compounds with significant binding and reuptake inhibition of the human dopamine transporter.
AB - A series of 3-carbomethoxy-4-(aryl-substituted)piperidines with various aryl groups were synthesized and examined for binding and reuptake inhibition at the human dopamine transporter, the human serotonin transporter, and the human norepinephrine transporter. The binding potency and reuptake inhibition efficacy was compared with that of (-)-cocaine to determine the significance of removing the two-carbon bridge of the cocaine nucleus on the inhibition of transporter binding and reuptake. Of the transporters examined, the substituted piperidines were relatively selective for the human dopamine transporter. In all cases examined, the cis-diastereomer of the 3-carbomethoxy-4-(aryl-substituted)piperidine was observed to be a more potent inhibitor of the human dopamine transporter than the trans diastereomer. Based on the Ki (binding) and IC50 (reuptake inhibition) values obtained, the most potent inhibitor of the series was cis-3-carbomethoxy-4-(4′-chlorophenyl)piperidine, and this compound suppressed spontaneous- and cocaine-induced stimulation in non-habituated male Swiss-Webster mice. The conclusion is that substantial portions of the cocaine structure can be dissected away to provide compounds with significant binding and reuptake inhibition of the human dopamine transporter.
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U2 - 10.1016/S0968-0896(02)00528-X
DO - 10.1016/S0968-0896(02)00528-X
M3 - Article
C2 - 12538008
AN - SCOPUS:0037354849
SN - 0968-0896
VL - 11
SP - 775
EP - 780
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 5
ER -