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A series of novel σ 1 receptor ligands with a 4-(2aminoethyl)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 σ 1 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 Nsubstituents. 1-Methylpiperidines showed particular high σ 1 receptor affinity and selectivity over the σ 2 subtype, whilst piperidines with a proton, a tosyl moiety or an ethyl moiety exhibited considerably lower σ 1 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 σ 1 receptor affinities. Recorded logD 7.4 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 σ 1 antagonist haloperidol. 1-Methylpiperidines 20a, 21a and 22a showed stronger antiproliferative effects on androgen negative human prostate cancer cells DU145 than the σ 1 ligands NE100 and S1RA.