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

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

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24 Citations (Scopus)

Abstract

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
Volume56
Issue number23
Pages (from-to)9709-24
Number of pages16
ISSN0022-2623
DOIs
Publication statusPublished - 12 Dec 2013

Keywords

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

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