Synthesis, docking and pharmacological evaluation of novel homo- and hetero-bis 3-piperazinylpropylindole derivatives at SERT and 5-HT1A receptor

doi:10.1016/j.bmc.2013.10.036

Bioorganic & Medicinal Chemistry

Volume 21, Issue 24, 15 December 2013, Pages 7604-7611

https://doi.org/10.1016/j.bmc.2013.10.036 Get rights and content

Abstract

A series of 3-(3-(4-(3-(1H-indol-3-yl)propyl)piperazin-1-yl)propyl)-1H-indole derivatives (3a–d and 5a–f) as homo- and hetero-bis-ligands, were synthesized and evaluated for in vitro affinity at the serotonin transporter (SERT) and the 5-HT_1A receptor. Compounds 5b and 5f showed nanomolar affinities for both targets. The experimental data were rationalized according to results obtained from docking experiments. These findings are in agreement with our proposal that bis-indole derivatives can bind both targets, and might serve as leads in the quest of ligands endowed with a dual mechanism of action.

Graphical abstract

Introduction

Selective serotonin (5-HT) reuptake inhibitors (SSRIs, e.g., citalopram, fluoxetine or paroxetine) are drugs widely prescribed for patients suffering from depression and several other psychiatric disorders.¹ Despite the therapeutic usefulness and safety of these drugs, they still display significant side effects. In addition, as with other antidepressants, they exhibit a delayed onset of action, requiring at least 2–4 weeks of treatment before the appearance of clinical effects. More than a decade ago, it was shown that this delayed onset of action can be overcome in humans by the combined use of a SSRI plus pindolol, a 5-HT_1A receptor antagonist.² This evidence has prompted the search of novel compounds exhibiting affinity for both the 5-HT transporter (SERT) and the 5-HT_1A receptor.³

The design of bivalent ligands, that is, compounds containing two receptor-interacting moieties linked by a flexible chain, has been proposed as a strategy for the development of novel compounds that can act simultaneously on two different targets.⁴

As part of our ongoing efforts searching for leads to the development of novel centrally acting agents, we have recently reported a 3-arylpiperazinylpropylindole series displaying affinity in the low nanomolar range for the 5-HT_1A receptor.⁵ Considering that indole derivatives bearing electron-withdrawing groups at C5 are well-known SERT ligands,³ we have designed a series of 5-substituted bis-indole derivatives connected by a propylpiperazine chain linker, with the idea that these compounds should exhibit dual activity, showing similarly high affinity at both the SERT and the 5-HT_1A receptor.

Section snippets

Chemistry

The synthesis of the C5-substituted homo-bis 3-(3-(4-(3-(1H-indol-3-yl)propyl)piperazin-1-l)propyl)-1H-indoles 3(a–d) is outlined in Scheme 1. Fischer indole synthesis from commercially available 4-phenylhydrazines using 3,4-dihydropyran under reflux conditions in acidic medium provided the corresponding indolylpropanols (1a–d) in good yield.⁶ This reaction proceeds by ring opening of the dihydropyrane ring under acid medium to provide in equilibrium the 4-hydroxy-butanal as intermediate, which

Conclusions

It is worth pointing out that at the least two compounds (5b and 5f) showed high and similar affinities for the SERT and the 5-HT_1A receptor. This result is in agreement with our proposal that bis-indole derivatives can bind both targets, and could serve as leads in the quest of ligands with a dual mechanism of action. Conversely, compounds 3a, 3b, 5c–e exhibited a clear selectivity for the SERT. It is worth mentioning that this diversity of effects was obtained with a small and relatively

Chemistry

Melting points were determined on a hot-stage apparatus and are uncorrected. The IR spectra were recorded in KBr discs on an FT-IR Bruker IFS 55 spectrophotometer and wavenumbers are reported in cm⁻¹. The ¹H and ¹³C NMR spectra were obtained on a Bruker DRX-300 spectrometer (300 and 75 MHz, respectively) in CDCl₃ or DMSO-d₆. Chemical shifts were recorded in ppm (δ) relative to TMS as an internal standard. J values are given in Hz. Microanalyses were carried out on a Fisons EA 1108 analyzer. High

Acknowledgments

We thank Dr. B. K. Cassels for critical reading of the manuscript. This work was partially funded by FONDECYT Grants 1090169 and 1130347 to HP-M, 1090037 and 1130185 to MR-P, 1100542 to PI-V and 11085002 to AF.

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Synthesis, docking and pharmacological evaluation of novel homo- and hetero-bis 3-piperazinylpropylindole derivatives at SERT and 5-HT1A receptor

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusions

Chemistry

Acknowledgments

Trends Neurosci.

Br. J. Anaesth.

Bioorg. Med. Chem.

J. Mol. Biol.

Annu. Rev. Clin. Psychol.

Curr. Med. Chem.

Chem. Pharm. Bull.

Org. Lett.

J. Med. Chem.

Nature

Science

J. Med. Chem.

Synthesis, docking and pharmacological evaluation of novel homo- and hetero-bis 3-piperazinylpropylindole derivatives at SERT and 5-HT_1A receptor