Structure-activity relationships of substituted N-benzyl piperidines in the GBR series: Synthesis of 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(2-trifluoromethylbenzyl)piperidine, an allosteric modulator of the serotonin transporter.
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)piperidine (the C(2)-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.
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Terrence L
TL
Boos
Elisabeth
E
Greiner
W Jason
WJ
Calhoun
Thomas E
TE
Prisinzano
Barbara
B
Nightingale
Christina M
CM
Dersch
Richard B
RB
Rothman
Arthur E
AE
Jacobson
Kenner C
KC
Rice
D000494:Allosteric Regulation / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C504158:4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(2-trifluoromethylbenzyl)piperidine; D001559:Benzhydryl Compounds; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines; D010880:Piperidines; D050486:Serotonin Plasma Membrane Transport Proteins; C043425:vanoxerine; C010045:N-benzoylpiperidine