Spirocyclic scaffolds play an increasing role in drug discovery as they define a rigid three-dimensional space to increase specific interactions with protein binding sites. Herein, a spirocyclic center was introduced into the lead compound 1 to rigidify its flexible benzylaminoethyl side chain. The key step of the synthesis was the reaction of different α,β-unsaturated amides 6 and 13–16 with methyl acrylate in the presence of TBDMSOTf. DFT calculations explain the mechanism of this transformation as concerted Diels–Alder reaction (functionals B3LYP and TPSS) or double (aza)-Michael addition (functionals PBE and wB97X-D). After separation of the diastereomeric spirocyclic products 8 and 17–20, LiAlH₄ reduction provided the spirocyclic hydroxymethyl piperidines 21a,b–25a,b showing low nanomolar σ₁ affinity (K_i < 100 nM). trans-Configured ligands (a-series) showed higher or equal σ₁ affinity and higher selectivity over σ₂ receptors and GluN2B-NMDA receptors than their cis-configured analogs (b-series). The additional hydroxymethyl moiety brings the log D_7.4 value in a promising range. The high σ₁ affinity (K_i = 3.6 nM) and the low lipophilicity result in the highest lipophilic ligand efficiency for the dispiro compound 23a (LLE = 6.0). The spirocyclic compounds reported herein and in particular the dispiro compound 23a demonstrate that ligands containing a large number of sp³ C-atoms possess favorable pharmacological (σ₁ receptor affinity, receptor selectivity) and physicochemical properties (log D_7.4 value) resulting in promising LLE.