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Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ1 Receptor Ligands with Antiproliferative Properties.
Holtschulte, Catharina; Börgel, Frederik; Westphälinger, Stefanie; Schepmann, Dirk; Civenni, Gianluca; Laurini, Erik; Marson, Domenico; Catapano, Carlo V; Pricl, Sabrina; Wünsch, Bernhard.
Afiliação
  • Holtschulte C; Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
  • Börgel F; Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
  • Westphälinger S; Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
  • Schepmann D; Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
  • Civenni G; Institute of Oncology Research, Università della Svizzera Italiana (USI), Via Vincenzo Vela 6, 6500, Bellinzona, Switzerland.
  • Laurini E; Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127, Trieste, Italy.
  • Marson D; Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127, Trieste, Italy.
  • Catapano CV; Institute of Oncology Research, Università della Svizzera Italiana (USI), Via Vincenzo Vela 6, 6500, Bellinzona, Switzerland.
  • Pricl S; Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127, Trieste, Italy.
  • Wünsch B; Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-237, Lodz, Poland.
ChemMedChem ; 17(7): e202100735, 2022 04 05.
Article em En | MEDLINE | ID: mdl-35077612
A series of novel σ1 receptor ligands with a 4-(2-aminoethyl)piperidine scaffold was prepared and biologically evaluated. The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent σ1 ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin-4(1H)-ones 7, homologation of the ketones 8 and introduction of diverse amino moieties and piperidine N-substituents. 1-Methylpiperidines showed particular high σ1 receptor affinity and selectivity over the σ2 subtype, whilst piperidines with a proton, a tosyl moiety or an ethyl moiety exhibited considerably lower σ1 affinity. Molecular dynamics simulations with per-residue binding free energy deconvolution demonstrated that different interactions of the basic piperidine-N-atom 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 σ1 receptor affinities. Recorded logD7.4 and calculated clogP values of 4a and 18a indicate low lipophilicity and thus high lipophilic ligand efficiency. Piperidine 4a inhibited the growth of human non-small cell lung cancer cells A427 to a similar extent as the σ1 antagonist haloperidol. 1-Methylpiperidines 20a, 21a and 22a showed stronger antiproliferative effects on androgen negative human prostate cancer cells DU145 than the σ1 ligands NE100 and S1RA.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperidinas / Receptores sigma / Antineoplásicos Limite: Humans / Male Idioma: En Revista: ChemMedChem Assunto da revista: FARMACOLOGIA / QUIMICA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperidinas / Receptores sigma / Antineoplásicos Limite: Humans / Male Idioma: En Revista: ChemMedChem Assunto da revista: FARMACOLOGIA / QUIMICA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Alemanha