title: Synthesis of 3,7-disubstituted imipramines by palladium-catalysed amination/cyclisation and evaluation of their inhibition of monoamine transporters.
abstract: We describe a novel approach for the synthesis of a series of 3,7-difunctionalised symmetric and unsymmetrical analogues of the tricyclic antidepressant (TCA) imipramine, which uses a key palladium-catalysed amination/cyclisation of an ester-functionalised dibromide. Of the ester, methyl, hydroxymethyl and methoxymethyl disubstituted compounds prepared, 3,7-dimethyl-imipramine was found to be the most potent against the human serotonin transporter (hSERT). The inhibitory potency of 3,7-dimethyl imipramine was found to be at least as high as the parent imipramine. This novel TCA also exhibits an increased selectivity (relative to imipramine) in binding to hSERT versus the human norepinephrine transporter (hNET). Even higher selectivity could be obtained with 3,7-dihydroxymethyl imipramine, which was found to be 167-fold more selective for hSERT over hNET, representative of a 120-fold gain in selectivity relative to the parent imipramine. These results further validate our previous model for the binding of imipramine and high-affinity analogues of imipramine to the central binding site of hSERT.
authors.affiliation: Department of Chemistry, Aarhus University, Denmark.
authors.forename: Helle
authors.initials: H
authors.lastname: Christensen
authors.forename: Christina
authors.initials: C
authors.lastname: Schjøth-Eskesen
authors.forename: Marie
authors.initials: M
authors.lastname: Jensen
authors.forename: Steffen
authors.initials: S
authors.lastname: Sinning
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Jensen
mesh_terms: D000586:Amination; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D003500:Cyclization; D003863:Depression / Q000188:drug therapy; D006801:Humans; D007099:Imipramine / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D010165:Palladium / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D007099:Imipramine; D010165:Palladium; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors