Synthesis and structure-affinity relationships of spirocyclic σ1 receptor ligands with tetrahydropyran scaffold
Year: 2024
Type: article
Abstract: The σ 1 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 σ 1 receptor ligands with different substituents in 4- and 9-position were synthesized and investigated for their σ 1 receptor affinity and selectivity over related targets. The σ 1 affinity of the ligands was correlated with their lipophilicity (log D 7.4 value) giving insight into their lipophilic ligand efficiency (LLE). The (pyridin-3-yl)methyl derivative 5i showed a promising balance of high σ 1 affinity ( K i (σ 1 ) = 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 σ 1 affinity ( K i ( 5a ) = 1.2 nM, K i ( 23a ) = 0.42 nM) and selectivity over σ 2 receptors ( 5a : 45-fold, 23a : 150-fold). • Tetrahydropyrans with a spirocyclic attached piperidine or azepane ring as novel σ 1 ligands. • Key steps of the synthesis are a Prins reaction and a Suzuki coupling. • Relationships between the structure and σ 1 affinity and selectivity are identified. • Pharmacokinetic parameters were determined. • Efficiency of the ligands with respect to their recorded lipophilicity (LLE)
Authors: Tobias Winge, Dirk Schepmann, Judith Schmidt, Bernhard Wünsch
Institution: University of Münster
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,850
Funder: Deutsche Forschungsgemeinschaft
OpenAlex ID: W4403809075