Novel 1,4-Dihydropyridine Derivatives as Mineralocorticoid Receptor Antagonists
The mineralocorticoid receptor (MR) belongs to the steroid receptor subfamily of nuclear receptors. MR is a transcription factor key in regulating blood pressure and mineral homeostasis. In addition, it plays an important role in a broad range of biological and pathological conditions, greatly expan...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/2439 |
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| author | Felipe Luis Pérez-Gordillo Natalia Serrano-Morillas Luz Marina Acosta-García María Teresa Aranda Daniela Passeri Roberto Pellicciari María Jesús Pérez de Vega Rosario González-Muñiz Diego Alvarez de la Rosa Mercedes Martín-Martínez |
| author_facet | Felipe Luis Pérez-Gordillo Natalia Serrano-Morillas Luz Marina Acosta-García María Teresa Aranda Daniela Passeri Roberto Pellicciari María Jesús Pérez de Vega Rosario González-Muñiz Diego Alvarez de la Rosa Mercedes Martín-Martínez |
| author_sort | Felipe Luis Pérez-Gordillo |
| collection | DOAJ |
| description | The mineralocorticoid receptor (MR) belongs to the steroid receptor subfamily of nuclear receptors. MR is a transcription factor key in regulating blood pressure and mineral homeostasis. In addition, it plays an important role in a broad range of biological and pathological conditions, greatly expanding its interest as a pharmacological target. Non-steroidal MR antagonists (MRAs) are of particular interest to avoid side effects and achieve tissue-specific modulation of the receptor. The 1,4-dihydropyridine (1,4-DHP) ring has been identified as an appropriate scaffold to develop non-steroidal MRAs. We report the identification of a novel series of 1,4-DHP that has been guided by structure-based drug design, focusing on the less explored DHP position 2. Interestingly, substituents at this position might interfere with MR helix H12 disposition, which is essential for the recruitment of co-regulators. Several of the newly synthesized 1,4-DHPs show interesting properties as MRAs and have a good selectivity profile. These 1,4-DHPs promote MR nuclear translocation with less efficiency than the natural agonist aldosterone, which explains, at least in part, its antagonist character. Molecular dynamic studies are suggestive of several derivatives interfering with the disposition of H12 in the agonist-associated conformation, and thus, they might stabilize an MR conformation unable to recruit co-activators. |
| first_indexed | 2024-03-11T09:41:51Z |
| format | Article |
| id | doaj.art-6e8cd3c136404642802d317671352b6c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:41:51Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6e8cd3c136404642802d317671352b6c2023-11-16T16:57:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243243910.3390/ijms24032439Novel 1,4-Dihydropyridine Derivatives as Mineralocorticoid Receptor AntagonistsFelipe Luis Pérez-Gordillo0Natalia Serrano-Morillas1Luz Marina Acosta-García2María Teresa Aranda3Daniela Passeri4Roberto Pellicciari5María Jesús Pérez de Vega6Rosario González-Muñiz7Diego Alvarez de la Rosa8Mercedes Martín-Martínez9Instituto de Química Médica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, SpainDepartamento de Ciencias Médicas Básicas and Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38200 La Laguna, SpainDepartamento de Ciencias Médicas Básicas and Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38200 La Laguna, SpainInstituto de Química Médica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, SpainTes Pharma, Via P. Togliatti 20, 06073 Corciano, ItalyTes Pharma, Via P. Togliatti 20, 06073 Corciano, ItalyInstituto de Química Médica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, SpainInstituto de Química Médica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, SpainDepartamento de Ciencias Médicas Básicas and Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38200 La Laguna, SpainInstituto de Química Médica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, SpainThe mineralocorticoid receptor (MR) belongs to the steroid receptor subfamily of nuclear receptors. MR is a transcription factor key in regulating blood pressure and mineral homeostasis. In addition, it plays an important role in a broad range of biological and pathological conditions, greatly expanding its interest as a pharmacological target. Non-steroidal MR antagonists (MRAs) are of particular interest to avoid side effects and achieve tissue-specific modulation of the receptor. The 1,4-dihydropyridine (1,4-DHP) ring has been identified as an appropriate scaffold to develop non-steroidal MRAs. We report the identification of a novel series of 1,4-DHP that has been guided by structure-based drug design, focusing on the less explored DHP position 2. Interestingly, substituents at this position might interfere with MR helix H12 disposition, which is essential for the recruitment of co-regulators. Several of the newly synthesized 1,4-DHPs show interesting properties as MRAs and have a good selectivity profile. These 1,4-DHPs promote MR nuclear translocation with less efficiency than the natural agonist aldosterone, which explains, at least in part, its antagonist character. Molecular dynamic studies are suggestive of several derivatives interfering with the disposition of H12 in the agonist-associated conformation, and thus, they might stabilize an MR conformation unable to recruit co-activators.https://www.mdpi.com/1422-0067/24/3/2439MRnuclear receptorNR3C2aldosteroneDHPantagonist |
| spellingShingle | Felipe Luis Pérez-Gordillo Natalia Serrano-Morillas Luz Marina Acosta-García María Teresa Aranda Daniela Passeri Roberto Pellicciari María Jesús Pérez de Vega Rosario González-Muñiz Diego Alvarez de la Rosa Mercedes Martín-Martínez Novel 1,4-Dihydropyridine Derivatives as Mineralocorticoid Receptor Antagonists International Journal of Molecular Sciences MR nuclear receptor NR3C2 aldosterone DHP antagonist |
| title | Novel 1,4-Dihydropyridine Derivatives as Mineralocorticoid Receptor Antagonists |
| title_full | Novel 1,4-Dihydropyridine Derivatives as Mineralocorticoid Receptor Antagonists |
| title_fullStr | Novel 1,4-Dihydropyridine Derivatives as Mineralocorticoid Receptor Antagonists |
| title_full_unstemmed | Novel 1,4-Dihydropyridine Derivatives as Mineralocorticoid Receptor Antagonists |
| title_short | Novel 1,4-Dihydropyridine Derivatives as Mineralocorticoid Receptor Antagonists |
| title_sort | novel 1 4 dihydropyridine derivatives as mineralocorticoid receptor antagonists |
| topic | MR nuclear receptor NR3C2 aldosterone DHP antagonist |
| url | https://www.mdpi.com/1422-0067/24/3/2439 |
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