TY - JOUR
T1 - Structure-activity relationships of substituted N-benzyl piperidines in the GBR series
T2 - Synthesis of 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(2-trifluoromethylbenzyl)piper idine, an allosteric modulator of the serotonin transporter
AU - Boos, Terrence L.
AU - Greiner, Elisabeth
AU - Calhoun, W. Jason
AU - Prisinzano, Thomas E.
AU - Nightingale, Barbara
AU - Dersch, Christina M.
AU - Rothman, Richard B.
AU - Jacobson, Arthur E.
AU - Rice, Kenner C.
N1 - Funding Information:
This research was supported by the NIH Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute on Drug Abuse. We (LMC, NIDDK) also thank the National Institute on Drug Abuse, NIH, DHHS, for partial support of this work. We also thank Victor Livengood (NIDDK) and Noel Whittaker (Department of Chemistry and Biochemistry, College of Chemical and Life Sciences, University of Maryland, College Park, MD) for the mass spectral data.
PY - 2006/6/1
Y1 - 2006/6/1
N2 - A series of 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-(substituted benzyl) piperidines with substituents at the ortho and meta positions in the aromatic ring of the N-benzyl side chain were synthesized and their affinities and selectivities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) were determined. One analogue, 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(2-trifluoromethylbenzyl)piper idine (the C2-trifluoromethyl substituted compound), has been found to act as an allosteric modulator of hSERT binding and function. It had little affinity for any of the transporters. Several compounds showed affinity for the DAT in the low nanomolar range and displayed a broad range of SERT/DAT selectivity ratios and very little affinity for the NET. The pharmacological tools provided by the availability of compounds with varying transporter affinity and selectivity could be used to obtain additional information about the properties a compound should have to act as a useful pharmacotherapeutic agent for cocaine addiction and help unravel the pharmacological mechanisms relevant to stimulant abuse.
AB - A series of 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-(substituted benzyl) piperidines with substituents at the ortho and meta positions in the aromatic ring of the N-benzyl side chain were synthesized and their affinities and selectivities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) were determined. One analogue, 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(2-trifluoromethylbenzyl)piper idine (the C2-trifluoromethyl substituted compound), has been found to act as an allosteric modulator of hSERT binding and function. It had little affinity for any of the transporters. Several compounds showed affinity for the DAT in the low nanomolar range and displayed a broad range of SERT/DAT selectivity ratios and very little affinity for the NET. The pharmacological tools provided by the availability of compounds with varying transporter affinity and selectivity could be used to obtain additional information about the properties a compound should have to act as a useful pharmacotherapeutic agent for cocaine addiction and help unravel the pharmacological mechanisms relevant to stimulant abuse.
KW - Allosteric inhibitor
KW - Cocaine treatment agent
KW - DAT, SERT, NET transporters
KW - N-Benzyl GBR analogue synthesis
KW - SAR
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U2 - 10.1016/j.bmc.2006.01.065
DO - 10.1016/j.bmc.2006.01.065
M3 - Article
C2 - 16563775
AN - SCOPUS:33646468976
SN - 0968-0896
VL - 14
SP - 3967
EP - 3973
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 11
ER -