Investigating isoindoline, tetrahydroisoquinoline, and tetrahydrobenzazepine scaffolds for their sigma receptor binding properties.
Substituted norbenzomorphans are known to display high affinity and selectivity for the two sigma receptor (σR) subtypes. In order to study the effects of simplifying the structures of these compounds, a scaffold hopping strategy was used to design several novel sets of substituted isoindolines, tetrahydroisoquinolines and tetrahydro-2-benzazepines. The binding affinities of these new compounds for the sigma 1 (σ1R) and sigma 2 (σ2R) receptors were determined, and some analogs were identified that exhibit high affinity (Ki ≤ 25 nM) and significant selectivity (>10-fold) for σ1R or σ2R. The preferred binding modes of selected compounds for the σ1R are predicted by modeling studies, and the nature of substituents on the aromatic ring and the nitrogen atom of the bicyclic skeleton appears to affect the preferred binding orientation of σ1R-preferring ligands.
['Linkens|Kathryn|K|', 'Schmidt|Hayden R|HR|', 'Sahn|James J|JJ|', 'Kruse|Andrew C|AC|', 'Martin|Stephen F|SF|']
D001552:Benzazepines D006801:Humans D054833:Isoindoles D008024:Ligands D062105:Molecular Docking Simulation D011485:Protein Binding D017480:Receptors, sigma D013329:Structure-Activity Relationship D044005:Tetrahydroisoquinolines
Scaffold hopping Docking Receptor subtype selectivity Sigma 1 receptor (σ1R) Sigma 2 receptor (σ2R) Transmembrane protein 97 (TMEM97)