Design and synthesis of 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram) analogues as novel probes for the serotonin transporter S1 and S2 binding sites

Research output: Contribution to journalJournal articleResearchpeer-review

  • Ashwini K Banala
  • Peng Zhang
  • Per Plenge
  • George Cyriac
  • Theresa Kopajtic
  • Jonathan L Katz
  • Løland, Claus Juul
  • Amy Hauck Newman

The serotonin transporter (SERT) is the primary target for antidepressant drugs. The existence of a high affinity primary orthosteric binding site (S1) and a low affinity secondary site (S2) has been described, and their relation to antidepressant pharmacology has been debated. Herein, structural modifications to the N, 4, 5, and 4' positions of (±)citalopram (1) are reported. All of the analogues were SERT-selective and demonstrated that steric bulk was tolerated at the SERT S1 site, including two dimeric ligands (15 and 51). In addition, eight analogues were identified with similar potencies to S-1 for decreasing the dissociation of [(3)H]S-1 from the S1 site via allosteric modulation at S2. Both dimeric compounds had similar affinities for the SERT S1 site (Ki = 19.7 and 30.2 nM, respectively), whereas only the N-substituted analogue, 51, was as effective as S-1 in allosterically modulating the binding of [(3)H]S-1 via S2.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number23
Pages (from-to)9709-24
Number of pages16
Publication statusPublished - 12 Dec 2013

    Research areas

  • Allosteric Site, Animals, Binding Sites, Brain, COS Cells, Cercopithecus aethiops, Citalopram, Humans, Serotonin Plasma Membrane Transport Proteins

ID: 120074578