Novel Azido-Iodo Photoaffinity Ligands for the Human Serotonin Transporter Based on the Selective Serotonin Reuptake Inhibitor (S)-Citalopram

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• 作者：Vivek Kumar ; Nageswari Yarravarapu ; David J. Lapinsky ; Danielle Perley ; Bruce Felts ; Michael J. Tomlinson ; Roxanne A. Vaughan ; L. Keith Henry ; John R. Lever ; Amy Hauck Newman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 23, 2015
• 年：2015
• 卷：58
• 期：14
• 页码：5609-5619
• 全文大小：460K
• ISSN：1520-4804

文摘

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鈥?27 nM) for hSERT, as assessed by [³H]5-HT transport inhibition. When tested against Ser438Thr hSERT, all three PALs showed dramatic rightward shifts in inhibitory potency, with K_i values ranging from 3.8 to 9.9 渭M, 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 [¹²⁵I]15 compared to that by [¹²⁵I]22 and [¹²⁵I]26 suggests differences in binding mode(s). These radioligands will be useful for characterizing the drug鈥損rotein binding interactions for (S)-citalopram at hSERT.