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

Tobias Winge; Dirk Schepmann; Judith Schmidt; Bernhard Wünsch

doi:10.1016/j.ejmech.2024.117002

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

Eur J Med Chem. 2024 Oct 26:281:117002. doi: 10.1016/j.ejmech.2024.117002. Online ahead of print.

Authors

Tobias Winge¹, Dirk Schepmann¹, Judith Schmidt¹, Bernhard Wünsch²

Affiliations

¹ Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, Corrensstraße 48, D-48149, Münster, Germany.
² Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, Corrensstraße 48, D-48149, Münster, Germany. Electronic address: wuensch@uni-muenster.de.

PMID: 39547080
DOI: 10.1016/j.ejmech.2024.117002

Abstract

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).

Keywords: LLE value; Lipophilicity; Metabolic stability; Plasma protein binding; Prins reaction; Receptor selectivity; Reductive alkylation; Rigidization; Spirocyclic piperidines; Stereochemistry; Structure affinity relationships; Suzuki coupling; sp(3) rich scaffolds; σ receptors; σ(1) receptor affinity.