Bis-hydrophobic 5-(1,2-dithiolan-3-yl)pentanamide budding leads targeting brain sigma-1 receptors.

Multi-mechanistic sigma-1 (σ1) receptors are implicated in several neurodegenerative pathologies including Alzheimer's disease (AD). As part of an ongoing effort to create a collection of diverse, readily synthesizable, σ1 acting small molecules for anti-neurodegenerative applications, we opted to try lipoic acid (LA) derived amides. These amides are designated as "5-(1,2 dithiolan-3-yl)pentanamides" throughout this publication. Our design approach was σ1 pharmacophore based - that is, ligands possessing three key functionalities (a hydrophobic dithiolane group, a flexible amide H-bonding linker, a hydrophobic alkyl/aryl group). Twenty-one dithiolane pentanamides were therefore designed, docked, synthesized, and pharmacologically assessed for σ1/σ2 binding affinities. Compounds 2, 6, 17 possessed promising selective σ1 binding affinities (with respective Ki values of 256, 133 and 32 nM) versus the standard ligand PD144418 (Ki = 0.08 nM). The three compounds will be used as leads in follow-up structure activity optimizations.