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

Sid Topiol; Benny Bang-Andersen; Connie Sanchez; Per Plenge; Claus J Loland; Karsten Juhl; Krestian Larsen; Peter Bregnedal; Klaus P Bøgesø

doi:10.1016/j.bmcl.2016.12.037

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

Sid Topiol, Benny Bang-Andersen, Connie Sanchez, Per Plenge, Claus J Loland, Karsten Juhl, Krestian Larsen, Peter Bregnedal, Klaus P Bøgesø

Neuropharm and Genetics

7 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	27
Issue number	3
Pages (from-to)	470-478
Number of pages	9
ISSN	0960-894X
DOIs	https://doi.org/10.1016/j.bmcl.2016.12.037
Publication status	Published - 1 Feb 2017

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Topiol, S., Bang-Andersen, B., Sanchez, C., Plenge, P., Loland, C. J., Juhl, K., Larsen, K., Bregnedal, P., & Bøgesø, K. P. (2017). 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. Bioorganic & Medicinal Chemistry Letters, 27(3), 470-478. https://doi.org/10.1016/j.bmcl.2016.12.037

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. / Topiol, Sid; Bang-Andersen, Benny; Sanchez, Connie et al.

In: Bioorganic & Medicinal Chemistry Letters, Vol. 27, No. 3, 01.02.2017, p. 470-478.

Research output: Contribution to journal › Journal article › Research › peer-review

Topiol, S, Bang-Andersen, B, Sanchez, C, Plenge, P, Loland, CJ, Juhl, K, Larsen, K, Bregnedal, P & Bøgesø, KP 2017, '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', Bioorganic & Medicinal Chemistry Letters, vol. 27, no. 3, pp. 470-478. https://doi.org/10.1016/j.bmcl.2016.12.037

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abstract = "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.",

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AU - Bang-Andersen, Benny

AU - Sanchez, Connie

AU - Plenge, Per

AU - Loland, Claus J

AU - Juhl, Karsten

AU - Larsen, Krestian

AU - Bregnedal, Peter

AU - Bøgesø, Klaus P

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AB - 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.

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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

Abstract

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