Structure-activity relationships of substituted N-benzyl piperidines in the GBR series: Synthesis of 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(2-trifluoromethylbenzyl)piper idine, an allosteric modulator of the serotonin transporter

Terrence L. Boos, Elisabeth Greiner, W. Jason Calhoun, Thomas E. Prisinzano, Barbara Nightingale, Christina M. Dersch, Richard B. Rothman, Arthur E. Jacobson, Kenner C. Rice

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)3967-3973
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number11
DOIs
StatePublished - Jun 1 2006

Bibliographical note

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.

Funding

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.

FundersFunder number
National Institutes of Health (NIH)
U.S. Department of Health and Human Services
National Institute on Drug Abuse
National Institute of Diabetes and Digestive and Kidney DiseasesZ01DK059501

    Keywords

    • Allosteric inhibitor
    • Cocaine treatment agent
    • DAT, SERT, NET transporters
    • N-Benzyl GBR analogue synthesis
    • SAR

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine
    • Molecular Biology
    • Pharmaceutical Science
    • Drug Discovery
    • Clinical Biochemistry
    • Organic Chemistry

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