X-ray structure based evaluation of analogs of citalopram: Compounds with increased affinity and selectivity compared with R-citalopram for the allosteric site (S2) on hSERT

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• 作者：Sid Topiol^a ; ^{sid.topiol@3D-2drug.com} ; Benny Bang-Andersen^b ; Connie Sanchez^c ; Per Plenge^d ; Claus J. Loland^d ; Karsten Juhl^b ; Krestian Larsen^b ; Peter Bregnedal^e ; Klaus P. Bø ; gesø ; ^e
• 关键词：SERT ; serotonin transporter ; DAT ; dopamine transporter ; NAT ; noradrenaline transporter ; NSS ; neurotransmitter ; sodium symporter ; SSRI ; selective serotonin reuptake inhibitor ; TCA ; tricyclic antidepressant ; dDAT ; Drosophila melanogaster DAT ; LeuT ; leucine transporter
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：470-478
• 全文大小：2384 K
• 卷排序：27

文摘

The recent publication of X-ray structures of SERT includes structures with the potent antidepressant S-Citalopram (S-Cit). Earlier predictions of ligand binding at both a primary (S1) and an allosteric modulator site (S2), were confirmed. We provide herein examples of a series of Citalopram analogs, showing distinct structure-activity relationship (SAR) at both sites that is independent of the SAR at the other site. Analogs with a higher affinity and selectivity than benchmark R-Citalopram (R-Cit) for the S2 versus the S1 site were identified. We deploy structural and computational analyses to explain this SAR and demonstrate the potential utility of the newly emerging X-ray structures within the neurotransmitter:sodium Symporter family for drug design.