X-ray structure based evaluation of analogs of citalopram: Compounds with increased affinity and selectivity compared with R-citalopram for the allosteric site (S2) on hSERT

Research output: Contribution to journalJournal articleResearchpeer-review

  • Sid Topiol
  • Benny Bang-Andersen
  • Connie Sanchez
  • Per Plenge
  • Løland, Claus Juul
  • Karsten Juhl
  • Krestian Larsen
  • Peter Bregnedal
  • Klaus P Bøgesø

The recent publication of X-ray structures of SERT includes structures with the potent antidepressant S-Citalopram (S-Cit). Earlier predictions of ligand binding at both a primary (S1) and an allosteric modulator site (S2), were confirmed. We provide herein examples of a series of Citalopram analogs, showing distinct structure-activity relationship (SAR) at both sites that is independent of the SAR at the other site. Analogs with a higher affinity and selectivity than benchmark R-Citalopram (R-Cit) for the S2 versus the S1 site were identified. We deploy structural and computational analyses to explain this SAR and demonstrate the potential utility of the newly emerging X-ray structures within the neurotransmitter:sodium Symporter family for drug design.

Original languageEnglish
JournalBioorganic & Medicinal Chemistry Letters
Issue number3
Pages (from-to)470-478
Number of pages9
Publication statusPublished - 1 Feb 2017

ID: 172849302