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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Banala AK,Zhang P,Plenge P,Cyriac G,Kopajtic T,Katz JL,Loland CJ,Newman AHdoi
10.1021/jm4014136subject
Has Abstractpub_date
2013-12-12 00:00:00pages
9709-24issue
23eissn
0022-2623issn
1520-4804journal_volume
56pub_type
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