title: Novel Azido-Iodo Photoaffinity Ligands for the Human Serotonin Transporter Based on the Selective Serotonin Reuptake Inhibitor (S)-Citalopram.
abstract: Three photoaffinity ligands (PALs) for the human serotonin transporter (hSERT) were synthesized based on the selective serotonin reuptake inhibitor (SSRI), (S)-citalopram (1). The classic 4-azido-3-iodo-phenyl group was appended to either the C-1 or C-5 position of the parent molecule, with variable-length linkers, to generate ligands 15, 22, and 26. These ligands retained high to moderate affinity binding (K(i) = 24-227 nM) for hSERT, as assessed by [(3)H]5-HT transport inhibition. When tested against Ser438Thr hSERT, all three PALs showed dramatic rightward shifts in inhibitory potency, with Ki values ranging from 3.8 to 9.9 μM, consistent with the role of Ser438 as a key residue for high-affinity binding of many SSRIs, including (S)-citalopram. Photoactivation studies demonstrated irreversible adduction to hSERT by all ligands, but the reduced (S)-citalopram inhibition of labeling by [(125)I]15 compared to that by [(125)I]22 and [(125)I]26 suggests differences in binding mode(s). These radioligands will be useful for characterizing the drug-protein binding interactions for (S)-citalopram at hSERT.
authors.affiliation: †Medicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.affiliation: ‡Division of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
authors.forename: Nageswari
authors.initials: N
authors.lastname: Yarravarapu
authors.affiliation: ‡Division of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lapinsky
authors.affiliation: §Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, United States.
authors.forename: Danielle
authors.initials: D
authors.lastname: Perley
authors.affiliation: §Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, United States.
authors.forename: Bruce
authors.initials: B
authors.lastname: Felts
authors.affiliation: §Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tomlinson
authors.affiliation: §Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, United States.
authors.forename: Roxanne A
authors.initials: RA
authors.lastname: Vaughan
authors.affiliation: §Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, United States.
authors.forename: L Keith
authors.initials: LK
authors.lastname: Henry
authors.affiliation: ∥Department of Radiology, University of Missouri, One Hospital Drive, Columbia, Missouri 65212, United States.|⊥Harry S. Truman Memorial Veterans' Hospital, 800 Hospital Drive, Columbia, Missouri 65201, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Lever
authors.affiliation: †Medicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
mesh_terms: D001386:Azides / Q000737:chemistry; D015283:Citalopram / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D055668:Photochemical Processes; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001386:Azides; D015283:Citalopram; D008024:Ligands; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors