Structure-activity relationships for a novel series of citalopram (1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile) analogues at monoamine transporters.
(+/-)-Citalopram (1, 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile), and its eutomer, escitalopram (S-(+)-1) are selective serotonin reuptake inhibitors (SSRIs) that are used clinically to treat anxiety and depression. To further explore structure-activity relationships at the serotonin transporter (SERT), a series of (+/-)-4- and 5-substituted citalopram analogues were designed, synthesized, and evaluated for binding at the SERT, dopamine transporter (DAT) and norepinephrine transporter (NET) in native rodent tissue. Many of these analogues showed high SERT binding affinities (Ki=1-40 nM) and selectivities over both NET and DAT. Selected enantiomeric pairs of analogues were synthesized and both retained enantioselectivity as with S- and R-1, wherein S>R at the SERT. In addition, the enantiomeric pairs of 1 and 5 were tested for binding at the homologous bacterial leucine transporter (LeuT), wherein low affinities and the absence of enantioselectivity suggested distinctive binding sites for these compounds at SERT as compared to LeuT. These novel ligands will provide molecular tools to elucidate drug-protein interactions at the SERT and to relate those to behavioral actions in vivo.
Zhang
Peng
P
Medicinal Chemistry Section, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, USA.
Cyriac
George
G
Kopajtic
Theresa
T
Zhao
Yongfang
Y
Javitch
Jonathan A
JA
Katz
Jonathan L
JL
Newman
Amy Hauck
AH
D026905:Amino Acid Transport Systems / Q000737:chemistry; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D015283:Citalopram / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D007930:Leucine / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D026905:Amino Acid Transport Systems; D001426:Bacterial Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D015283:Citalopram; D007930:Leucine