{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:13:49Z","timestamp":1786119229712,"version":"build-2736575974"},"reference-count":54,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T00:00:00Z","timestamp":1773532800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T00:00:00Z","timestamp":1773532800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Hexahydroquinoline (HHQ) is a widely recognized scaffold that has garnered considerable attention owing to its diverse pharmacological properties. The structure of HHQ includes a 1,4\u2010dihydropyridine (DHP) ring, which serves as the pharmacophore for the predominant class of drugs known as calcium channel blockers. DHPs are frequently utilized in the management of cardiovascular diseases and also show potential for pain management. Since all DHPs on the market possess ester functionality, we aimed to employ bioisosteric replacement to observe if their amide\u2010containing counterparts would still block calcium channels. Therefore, we synthesized new HHQs with ester or amide functionality (\n                    <jats:bold>EM1<\/jats:bold>\n                    \u2010\n                    <jats:bold>EM15<\/jats:bold>\n                    ) and investigated their effects on L\u2010(Ca\n                    <jats:sub>v<\/jats:sub>\n                    1.2) and T\u2010(Ca\n                    <jats:sub>v<\/jats:sub>\n                    3.2)\u2010type calcium channels using the whole\u2010cell patch clamp technique. Although the amide derivatives were somewhat less effective than their ester counterparts, they still blocked calcium channels to a significant degree. Retesting\n                    <jats:bold>EM4<\/jats:bold>\n                    enantiomers on two types of calcium channels demonstrated that the (\n                    <jats:italic>R<\/jats:italic>\n                    )\u2010isomer was more responsible for the blocking activity in both cases. Molecular docking and molecular dynamics simulations demonstrated that\n                    <jats:bold>(<\/jats:bold>\n                    <jats:italic>\n                      <jats:bold>R<\/jats:bold>\n                    <\/jats:italic>\n                    <jats:bold>)\u2010EM4<\/jats:bold>\n                    and\n                    <jats:bold>(<\/jats:bold>\n                    <jats:italic>\n                      <jats:bold>R<\/jats:bold>\n                    <\/jats:italic>\n                    <jats:bold>)\u2010EM6<\/jats:bold>\n                    adopt binding modes in Ca\n                    <jats:sub>v<\/jats:sub>\n                    1.2 similar to amlodipine, while showing favorable stability. Docking studies in Ca\n                    <jats:sub>v<\/jats:sub>\n                    3.2 suggested that EM compounds bind within the \u2162\u2010\u2163 fenestration, a reported non\u2010selective DHP binding site. Furthermore, amide derivatives were found to be more metabolically stable based on the in vitro experiments conducted on rat microsomes. Overall, our study reveals HHQ with an amide group as a promising new scaffold for developing future calcium channel blockers for treating cardiovascular and pain conditions.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70261","type":"journal-article","created":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T17:20:46Z","timestamp":1773595246000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hexahydroquinoline Featuring Amide Functionality: A Promising Scaffold With Calcium Channel Blocking Activity"],"prefix":"10.1002","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0191-0746","authenticated-orcid":false,"given":"Ebru","family":"Ko\u00e7ak Aslan","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Hacettepe University Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Lam","sequence":"additional","affiliation":[{"name":"Molecular Design Group, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy Freie Universit\u00e4t Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute University of Calgary Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5168-3866","authenticated-orcid":false,"given":"G\u00f6knil Pelin","family":"Co\u015fkun","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Ac\u0131badem University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0902-3394","authenticated-orcid":false,"given":"Ay\u015fe","family":"Karag\u00fczel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Hacettepe University Ankara Turkey"},{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Ba\u015fkent University Ba\u011fl\u0131ca Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Denzinger","sequence":"additional","affiliation":[{"name":"Molecular Design Group, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy Freie Universit\u00e4t Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaan","family":"Birg\u00fcl","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Bah\u00e7e\u015fehir University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mert","family":"\u00dclgen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Ac\u0131badem University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan W.","family":"Nafie","sequence":"additional","affiliation":[{"name":"BioTools, Inc. West Palm Beach Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3765-3235","authenticated-orcid":false,"given":"Onur","family":"\u015eahin","sequence":"additional","affiliation":[{"name":"Department of Occupat Health &amp; Safety, Faculty of Health Sciences Sinop University Sinop Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0501-6231","authenticated-orcid":false,"given":"Daniel W.","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Department of Chemistry &amp; Biochemistry University of Texas at Arlington Arlington Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald W.","family":"Zamponi","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute University of Calgary Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5344-0048","authenticated-orcid":false,"given":"Gerhard","family":"Wolber","sequence":"additional","affiliation":[{"name":"Molecular Design Group, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy Freie Universit\u00e4t Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2287-9509","authenticated-orcid":false,"given":"Miyase G\u00f6zde","family":"G\u00fcnd\u00fcz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Hacettepe University Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114787"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2021.114233"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2019.103187"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.12968\/bjca.2019.14.2.64"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.15406\/japlr.2017.05.00148"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24108803"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-014-1566-3"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-013-1376-z"},{"key":"e_1_2_9_10_1","unstructured":"Bruker AXS Inc. 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