Synthesis and structure-affinity relationships of spirocyclic σ₁ receptor ligands with tetrahydropyran scaffold

The σ₁ receptor plays a key role in the regulation of various processes in the human body; it is involved in the development of neurodegenerative and neuropsychiatric diseases and is overexpressed in several human tumors rendering it an important target for potential drug candidates. In this project, spirocyclic σ₁ receptor ligands with different substituents in 4- and 9-position were synthesized and investigated for their σ₁ receptor affinity and selectivity over related targets. The σ₁ affinity of the ligands was correlated with their lipophilicity (logD_7.4 value) giving insight into their lipophilic ligand efficiency (LLE). The (pyridin-3-yl)methyl derivative 5i showed a promising balance of high σ₁ affinity (K_i(σ₁) = 3.9 nM) and selectivity (>250-fold) as well as high LLE of 5.8. 5i has a high plasma protein binding (89 %) and promising metabolic stability in the presence of mouse liver microsomes and NADPH (83 % intact after 90 min). Increasing the size of the piperidine ring of the spirocyclic ligands 5 to an azepane ring led to considerably increased σ₁ affinity (K_i(5a) = 1.2 nM, K_i(23a) = 0.42 nM) and selectivity over σ₂ receptors (5a: 45-fold, 23a: 150-fold).