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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.<\/jats:p>","DOI":"10.3390\/ijms24032439","type":"journal-article","created":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T01:58:59Z","timestamp":1674784739000},"page":"2439","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel 1,4-Dihydropyridine Derivatives as Mineralocorticoid Receptor Antagonists"],"prefix":"10.3390","volume":"24","author":[{"given":"Felipe Luis","family":"P\u00e9rez-Gordillo","sequence":"first","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Serrano-Morillas","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias M\u00e9dicas B\u00e1sicas and Instituto de Tecnolog\u00edas Biom\u00e9dicas, Universidad de La Laguna, 38200 La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luz Marina","family":"Acosta-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias M\u00e9dicas B\u00e1sicas and Instituto de Tecnolog\u00edas Biom\u00e9dicas, Universidad de La Laguna, 38200 La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Teresa","family":"Aranda","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Passeri","sequence":"additional","affiliation":[{"name":"Tes Pharma, Via P. Togliatti 20, 06073 Corciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Pellicciari","sequence":"additional","affiliation":[{"name":"Tes Pharma, Via P. Togliatti 20, 06073 Corciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5095-5882","authenticated-orcid":false,"given":"Mar\u00eda Jes\u00fas","family":"P\u00e9rez de Vega","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Gonz\u00e1lez-Mu\u00f1iz","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4324-2793","authenticated-orcid":false,"given":"Diego","family":"Alvarez de la Rosa","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias M\u00e9dicas B\u00e1sicas and Instituto de Tecnolog\u00edas Biom\u00e9dicas, Universidad de La Laguna, 38200 La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Mart\u00edn-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1126\/science.3037703","article-title":"Cloning of human mineralocorticoid receptor complementary DNA: Structural and functional kinship with the glucocorticoid receptor","volume":"237","author":"Arriza","year":"1987","journal-title":"Science"},{"key":"ref_2","first-page":"965","article-title":"The multifaceted mineralocorticoid receptor","volume":"4","year":"2014","journal-title":"Compr. 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