Structure-activity relationship studies of highly selective inhibitors of the dopamine transporter: N-benzylpiperidine analogues of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine

Elisabeth Greiner; Thomas Prisinzano; Edward M Johnson 2nd; Christina M Dersch; Jamila Marcus; John S Partilla; Richard B Rothman; Arthur E Jacobson; Kenner C Rice

doi:10.1021/jm020419v

Structure-activity relationship studies of highly selective inhibitors of the dopamine transporter: N-benzylpiperidine analogues of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine

J Med Chem. 2003 Apr 10;46(8):1465-9. doi: 10.1021/jm020419v.

Authors

Elisabeth Greiner¹, Thomas Prisinzano, Edward M Johnson 2nd, Christina M Dersch, Jamila Marcus, John S Partilla, Richard B Rothman, Arthur E Jacobson, Kenner C Rice

Affiliation

¹ Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, Maryland 20892, USA.

PMID: 12672246
DOI: 10.1021/jm020419v

Abstract

A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethyl-1-benzylpiperidines were examined for their ability to bind to the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). Binding results indicated that the presence of an electron-withdrawing group in the C(4)-position of the N-benzyl group is beneficial for binding to the DAT. Several analogues have been identified with high affinity for the DAT, up to 500-fold selectivity over the SERT and about 170-fold selectivity over the NET in binding and uptake inhibition assays.

MeSH terms

Carrier Proteins / metabolism
Dopamine / metabolism*
Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors
Dopamine Uptake Inhibitors / chemical synthesis*
Dopamine Uptake Inhibitors / chemistry
Dopamine Uptake Inhibitors / pharmacology
Membrane Glycoproteins / metabolism
Membrane Transport Modulators*
Membrane Transport Proteins / metabolism*
Nerve Tissue Proteins*
Norepinephrine / metabolism
Norepinephrine Plasma Membrane Transport Proteins
Piperazines / chemistry*
Piperidines / chemical synthesis*
Piperidines / chemistry
Piperidines / pharmacology
Protein Binding
Radioligand Assay
Serotonin / metabolism
Serotonin Plasma Membrane Transport Proteins
Structure-Activity Relationship
Symporters / antagonists & inhibitors
Symporters / metabolism

Substances

Carrier Proteins
Dopamine Plasma Membrane Transport Proteins
Dopamine Uptake Inhibitors
Membrane Glycoproteins
Membrane Transport Modulators
Membrane Transport Proteins
Nerve Tissue Proteins
Norepinephrine Plasma Membrane Transport Proteins
Piperazines
Piperidines
Serotonin Plasma Membrane Transport Proteins
Symporters
Serotonin
vanoxerine
Dopamine
Norepinephrine