Synthesis and structure-affinity relationships of spirocyclic 1 receptor ligands with tetrahydropyran scaffold.

T. Winge, D. Schepmann, J. Schmidt, B. Wünsch

Forschungsartikel (Zeitschrift) | Peer reviewed

Zusammenfassung

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 (logD7.4 value) giving insight into their lipophilic ligand efficiency (LLE). The (pyridin-3-yl)methyl derivative 5i showed a promising balance of high σ1 affinity (Ki(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 (Ki(5a) = 1.2 nM, Ki(23a) = 0.42 nM) and selectivity over σ2 receptors (5a: 45-fold, 23a: 150-fold).

Details zur Publikation

FachzeitschriftEuropean Journal of Medicinal Chemistry
Jahrgang / Bandnr. / Volume281
Artikelnummer117002
StatusVeröffentlicht
Veröffentlichungsjahr2025
Sprache, in der die Publikation verfasst istEnglisch
DOI10.1016/j.ejmech.2024.117002
Stichwörterσ receptors; σ1 receptor affinity; Receptor selectivity; Spirocyclic piperidines; sp3 rich scaffolds; Rigidization; Prins reaction; Suzuki coupling; Reductive alkylation; Stereochemistry; Lipophilicity; LLE value; Structure affinity relationships; Plasma protein binding; Metabolic stability

Autor*innen der Universität Münster

Wünsch, Bernhard
Professur für Pharmazeutische Chemie (Prof. Wünsch)