Synthesis and inhibitory evaluation of 3-linked imipramines for the exploration of the S2 site of the human serotonin transporter

Anne Brinkø; Maja Thim Larsen; Heidi Koldsø; Louise Morck Besenbacher; Anders Kolind; Birgit Schiøtt; Steffen Sinning; Henrik Helligsø Jensen

doi:10.1016/j.bmc.2016.04.039

Synthesis and inhibitory evaluation of 3-linked imipramines for the exploration of the S2 site of the human serotonin transporter

Anne Brinkø, Maja Thim Larsen, Heidi Koldsø, Louise Morck Besenbacher, Anders Kolind, Birgit Schiøtt, Steffen Sinning, Henrik Helligsø Jensen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

The human serotonin transporter is the primary target of several antidepressant drugs, and the importance of a primary, high affinity binding site (S1) for antidepressant binding is well documented. The existence of a lower affinity, secondary binding site (S2) has, however, been debated. Herein we report the synthesis of 3-position coupled imipramine ligands from clomipramine using a copper free Sonogashira reaction. Ligand design was inspired by results from docking and steered molecular dynamics simulations, and the ligands were utilized in a structure-activity relationship study of the positional relationship between the S1 and S2 sites. The computer simulations suggested that the S2 site does indeed exist although with lower affinity for imipramine than observed within the S1 site. Additionally, it was possible to dock the 3-linked imipramine analogs into positions which occupy the S1 and the S2 site simultaneously. The structure activity relationship study showed that the shortest ligands were the most potent, and mutations enlarging the proposed S2 site were found to affect the larger ligands positively, while the smaller ligands were mostly unaffected.

Original language	English
Journal	Bioorganic & Medicinal Chemistry
Volume	24
Issue	12
Pages (from-to)	2725-2738
Number of pages	14
ISSN	0968-0896
DOIs	https://doi.org/10.1016/j.bmc.2016.04.039
Publication status	Published - 21 Apr 2016

Keywords

Antidepressants
Bivalent ligands
Depression
Serotonin
Sonogashira coupling
Transporter

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title = "Synthesis and inhibitory evaluation of 3-linked imipramines for the exploration of the S2 site of the human serotonin transporter",

abstract = "The human serotonin transporter is the primary target of several antidepressant drugs, and the importance of a primary, high affinity binding site (S1) for antidepressant binding is well documented. The existence of a lower affinity, secondary binding site (S2) has, however, been debated. Herein we report the synthesis of 3-position coupled imipramine ligands from clomipramine using a copper free Sonogashira reaction. Ligand design was inspired by results from docking and steered molecular dynamics simulations, and the ligands were utilized in a structure-activity relationship study of the positional relationship between the S1 and S2 sites. The computer simulations suggested that the S2 site does indeed exist although with lower affinity for imipramine than observed within the S1 site. Additionally, it was possible to dock the 3-linked imipramine analogs into positions which occupy the S1 and the S2 site simultaneously. The structure activity relationship study showed that the shortest ligands were the most potent, and mutations enlarging the proposed S2 site were found to affect the larger ligands positively, while the smaller ligands were mostly unaffected.",

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author = "Anne Brink{\o} and Larsen, {Maja Thim} and Heidi Kolds{\o} and Besenbacher, {Louise Morck} and Anders Kolind and Birgit Schi{\o}tt and Steffen Sinning and Jensen, {Henrik Helligs{\o}}",

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Synthesis and inhibitory evaluation of 3-linked imipramines for the exploration of the S2 site of the human serotonin transporter. / Brinkø, Anne; Larsen, Maja Thim; Koldsø, Heidi et al.
In: Bioorganic & Medicinal Chemistry, Vol. 24, No. 12, 21.04.2016, p. 2725-2738.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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AU - Kolind, Anders

AU - Schiøtt, Birgit

AU - Sinning, Steffen

AU - Jensen, Henrik Helligsø

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Synthesis and inhibitory evaluation of 3-linked imipramines for the exploration of the S2 site of the human serotonin transporter

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