Studies on the affinity of 6-[(n-(cyclo)aminoalkyl)oxy]-4H-chromen-4-ones for sigma 1/2 receptors

Winnie Deuther-Conrad; Daniel Diez-Iriepa; Isabel Iriepa; Francisco López-Muñoz; María Angeles Martínez-Grau; Michael Gütschow; José Marco-Contelles

doi:10.1039/D1MD00105A

Studies on the affinity of 6-[(n-(cyclo)aminoalkyl)oxy]-4H-chromen-4-ones for sigma 1/2 receptors†

Winnie Deuther-Conrad,

*^a Daniel Diez-Iriepa,^b Isabel Iriepa,

^b Francisco López-Muñoz,^c María Angeles Martínez-Grau,^d Michael Gütschow

*^e and José Marco-Contelles

*^f

Author affiliations

* Corresponding authors

^a Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, 04318 Leipzig, Germany
E-mail: w.deuther-conrad@hzdr.de

^b Department of Organic and Inorganic Chemistry, University of Alcalá, Ctra. Madrid-Barcelona, Km. 33,6, 28871 Alcalá de Henares, Madrid, Spain

^c Faculty of Health, Camilo José Cela University of Madrid (UCJC), Spain; Neuropsychopharmacology Unit, “Hospital 12 de Octubre” Research Institute, Madrid, Spain

^d MG Drug Discovery Consulting, C/Nuria 28 2F, 28034 Madrid, Spain

^e Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
E-mail: guetschow@uni-bonn.de

^f Laboratory of Medicinal Chemistry, IQOG, CSIC, C/Juan de la Cierva 3, 28006 Madrid, Spain
E-mail: jlmarco@iqog.csic.es

Abstract

Sigma (σ) receptors represent attractive targets for the development of potential agents for the treatment of several disorders, including Alzheimer's disease and neuropathic pain. In the search for multitarget small molecules (MSMs) against such disorders, we have re-discovered chromenones as new affine σ₁/σ₂ ligands. 6-(4-(Piperidin-1-yl)butoxy)-4H-chromen-4-one (7), a previously identified MSM with potent dual-target activities against acetylcholinesterase and monoamine oxidase B, also exhibited σ₁/σ₂ affinity. 6-(3-(Azepan-1-yl)propoxy)-4H-chromen-4-one (20) showed a K_i value for σ₁ of 27.2 nM (selectivity (σ₁/σ₂) = 28), combining the desired σ₁ receptor affinity with a dual inhibitory capacity against both acetyl- and butyrylcholinesterase. 6-((5-Morpholinopentyl)oxy)-4H-chromen-4-one (12) was almost equipotent to S1RA, an established σ₁ receptor antagonist.

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Article information

DOI: https://doi.org/10.1039/D1MD00105A
Article type: Research Article
Submitted: 23 Mar 2021
Accepted: 05 May 2021
First published: 20 May 2021

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RSC Med. Chem., 2021,12, 1000-1004

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Studies on the affinity of 6-[(n-(cyclo)aminoalkyl)oxy]-4H-chromen-4-ones for sigma 1/2 receptors

W. Deuther-Conrad, D. Diez-Iriepa, I. Iriepa, F. López-Muñoz, M. A. Martínez-Grau, M. Gütschow and J. Marco-Contelles, RSC Med. Chem., 2021, 12, 1000 DOI: 10.1039/D1MD00105A

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RSC Medicinal Chemistry

Studies on the affinity of 6-[(n-(cyclo)aminoalkyl)oxy]-4H-chromen-4-ones for sigma 1/2 receptors†

Abstract

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Studies on the affinity of 6-[(n-(cyclo)aminoalkyl)oxy]-4H-chromen-4-ones for sigma 1/2 receptors

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