title: Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants.
abstract: To further explore the structure-activity relationships of conformationally constrained tropanes, a number of new biaryl and arylacetylene analogs were designed and synthesized. Some of these compounds such as 3a-b, 3d, 3f-h, 5b, and 7g were found to be highly potent and selective or mixed norepinephrine transporter (NET) inhibitors with Ki values of 0.8-9.4 nM. Moreover, all of these compounds display weak to extremely weak muscarinic receptor binding affinity, indicating that as potential antidepressants, they may overcome certain side effects that are of concern with other antidepressants, which are thought to be mediated by their anticholinergic properties.
authors.affiliation: Acenta Discovery, Inc., 9030 S. Rita Road, Suite 300, Tucson, AZ 85747-9101, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.forename: Thomas
authors.initials: T
authors.lastname: Kläss
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Giberson
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000114:Acetylene / Q000737:chemistry*; D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011487:Protein Conformation; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D027981:Symporters / Q000037:antagonists & inhibitors*; D014326:Tropanes / Q000737:chemistry*
chemical_list: D000928:Antidepressive Agents; D008024:Ligands; D050484:Norepinephrine Plasma Membrane Transport Proteins; D027981:Symporters; D014326:Tropanes; D000114:Acetylene