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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
- Source :
- Journal of Medicinal Chemistry. 56:9709-9724
- Publication Year :
- 2013
- Publisher :
- American Chemical Society (ACS), 2013.
-
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.
- Subjects :
- Steric effects
Stereochemistry
Allosteric regulation
Citalopram
Article
Chlorocebus aethiops
Drug Discovery
medicine
Animals
Humans
Binding site
Serotonin transporter
Serotonin Plasma Membrane Transport Proteins
Binding Sites
biology
Chemistry
Brain
Affinities
COS Cells
biology.protein
Molecular Medicine
Antidepressant
Allosteric Site
medicine.drug
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....a1ecf2ade7d007a7e57e35e96bbea336
- Full Text :
- https://doi.org/10.1021/jm4014136