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The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent \u03c3<jats:sub>1<\/jats:sub> ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin\u20104(1<jats:italic>H<\/jats:italic>)\u2010ones <jats:bold>7<\/jats:bold>, homologation of the ketones <jats:bold>8<\/jats:bold> and introduction of diverse amino moieties and piperidine N\u2010substituents. 1\u2010Methylpiperidines showed particular high \u03c3<jats:sub>1<\/jats:sub> receptor affinity and selectivity over the \u03c3<jats:sub>2<\/jats:sub> subtype, whilst piperidines with a proton, a tosyl moiety or an ethyl moiety exhibited considerably lower \u03c3<jats:sub>1<\/jats:sub> affinity. Molecular dynamics simulations with per\u2010residue binding free energy deconvolution demonstrated that different interactions of the basic piperidine\u2010N\u2010atom and its substituents (or the cyclohexane ring) with the lipophilic binding pocket consisting of Leu105, Thr181, Leu182, Ala185, Leu186, Thr202 and Tyr206 are responsible for the different \u03c3<jats:sub>1<\/jats:sub> receptor affinities. Recorded logD<jats:sub>7.4<\/jats:sub> and calculated clogP values of <jats:bold>4a<\/jats:bold> and <jats:bold>18a<\/jats:bold> indicate low lipophilicity and thus high lipophilic ligand efficiency. Piperidine <jats:bold>4a<\/jats:bold> inhibited the growth of human non\u2010small cell lung cancer cells A427 to a similar extent as the \u03c3<jats:sub>1<\/jats:sub> antagonist haloperidol. 1\u2010Methylpiperidines <jats:bold>20a<\/jats:bold>, <jats:bold>21a<\/jats:bold> and <jats:bold>22a<\/jats:bold> showed stronger antiproliferative effects on androgen negative human prostate cancer cells DU145 than the \u03c3<jats:sub>1<\/jats:sub> ligands NE100 and S1RA.<\/jats:p>","DOI":"10.1002\/cmdc.202100735","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T15:39:22Z","timestamp":1643125162000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Synthesis of Aminoethyl\u2010Substituted Piperidine Derivatives as \u03c3<sub>1<\/sub> Receptor Ligands with Antiproliferative Properties"],"prefix":"10.1002","volume":"17","author":[{"given":"Catharina","family":"Holtschulte","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Westf\u00e4lische Wilhelms-Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 48149 M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"B\u00f6rgel","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Westf\u00e4lische Wilhelms-Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 48149 M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Westph\u00e4linger","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Westf\u00e4lische Wilhelms-Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 48149 M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Schepmann","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Westf\u00e4lische Wilhelms-Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 48149 M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Civenni","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research Universit\u00e0 della Svizzera Italiana (USI)  Via Vincenzo Vela 6 6500 Bellinzona Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Laurini","sequence":"additional","affiliation":[{"name":"Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA University of Trieste  34127 Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Marson","sequence":"additional","affiliation":[{"name":"Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA University of Trieste  34127 Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo V.","family":"Catapano","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research Universit\u00e0 della Svizzera Italiana (USI)  Via Vincenzo Vela 6 6500 Bellinzona Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Pricl","sequence":"additional","affiliation":[{"name":"Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA University of Trieste  34127 Trieste Italy"},{"name":"Department of General Biophysics Faculty of Biology and Environmental Protection University of Lodz  90-237 Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9030-8417","authenticated-orcid":false,"given":"Bernhard","family":"W\u00fcnsch","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Westf\u00e4lische Wilhelms-Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 48149 M\u00fcnster Germany"},{"name":"Chemical biology of ion channels (Chembion) Westf\u00e4lische Wilhelms-Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 48149 M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,9]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S0022-3565(25)30536-7","volume":"197","author":"Martin W. 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