Deuther-Conrad_2021_RSC.Med.Chem_12_1000

Sigma (sigma) receptors represent attractive targets for the development of potential agents for the treatment of several disorders, including Alzheimer's disease and neuropathic pain. In the search for multitarget small molecules (MSMs) against such disorders, we have re-discovered chromenones as new affine sigma(1)/sigma(2) ligands. 6-(4-(Piperidin-1-yl)butoxy)-4H-chromen-4-one (7), a previously identified MSM with potent dual-target activities against acetylcholinesterase and monoamine oxidase B, also exhibited sigma(1)/sigma(2) affinity. 6-(3-(Azepan-1-yl)propoxy)-4H-chromen-4-one (20) showed a K (i) value for sigma(1) of 27.2 nM (selectivity (sigma(1)/sigma(2)) = 28), combining the desired sigma(1) receptor affinity with a dual inhibitory capacity against both acetyl- and butyrylcholinesterase. 6-((5-Morpholinopentyl)oxy)-4H-chromen-4-one (12) was almost equipotent to S1RA, an established sigma(1) receptor antagonist.