Diastereoselective synthesis and structure-affinity relationships of σ 1 receptor ligands with spirocyclic scaffold.

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, LiAlH 4 reduction provided the spirocyclic hydroxymethyl piperidines 21a,b-25a,b showing low nanomolar σ 1 affinity ( K i < 100 nM). trans -Configured ligands (a-series) showed higher or equal σ 1 affinity and higher selectivity over σ 2 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 σ 1 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 sp 3 C-atoms possess favorable pharmacological ( σ 1 receptor affinity, receptor selectivity) and physicochemical properties (log  D 7.4 value) resulting in promising LLE.