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.
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.
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
Ashwini K
AK
Banala
Peng
P
Zhang
Per
P
Plenge
George
G
Cyriac
Theresa
T
Kopajtic
Jonathan L
JL
Katz
Claus Juul
CJ
Loland
Amy Hauck
AH
Newman
D000495:Allosteric Site; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D015283:Citalopram / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D006801:Humans; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
D050486:Serotonin Plasma Membrane Transport Proteins; D015283:Citalopram