title: Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors.
abstract: 4-(4-Chlorophenyl)piperidine analogues each bearing a thioacetamide side chain appendage similar to that found in the wake-promoting drug modafinil have been synthesized. The transporter inhibitory activity of both the cis and trans isomers of these 3,4-disubstituted piperidines in both their (+)- and (-)-enantiomeric forms was determined. These studies reveal that the (-)-cis analogues exhibit dopamine transporter/norepinephrine transporter (DAT/NET) selectivity as was previously reported for the (+)-trans analogues. On the other hand, the (-)-trans and the (+)-cis isomers show serotonin transporter (SERT) or SERT/NET selectivity. Among them, (+)-cis-5b shows a low nanomolar Ki for the NET with 39-fold and 321-fold lower potency at the DAT and SERT, respectively, thus making it a useful pharmacological research tool for exploring NET-associated behavioral signatures. On the other hand, several of the compounds described herein, such as (+)-trans-5c, show comparable activity at all three transporters. Because broad-spectrum transporter inhibitors have been hypothesized to exhibit a more rapid onset of action and/or a greater efficacy as antidepressant agents than those selective for SERT or SERT + NET, some of the present compounds will be valuable to study in animal models of depression.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (M/C781), University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7230, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: He
authors.forename: Toru
authors.initials: T
authors.lastname: Kurome
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Giberson
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D008024:Ligands; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010880:Piperidines; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013440:Sulfides; C507630:2-((4-(4-chlorophenyl)-1-methylpiperidin-3-yl)methylsulfanyl)-N-methylacetamide