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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

Authors :
Ashwini K. Banala
Peng Zhang
Theresa A. Kopajtic
Per Plenge
George Cyriac
Amy Hauck Newman
Claus J. Loland
Jonathan L. Katz
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.

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