Studies on the affinity of 6-[(n-(cyclo)aminoalkyl)oxy]-4H-chromen-4-ones for sigma 1/2 receptors.

Sigma (σ) 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 σ(1)/σ(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 σ(1)/σ(2) affinity. 6-(3-(Azepan-1-yl)propoxy)-4H-chromen-4-one (20) showed a K (i) value for σ(1) of 27.2 nM (selectivity (σ(1)/σ(2)) = 28), combining the desired σ(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 σ(1) receptor antagonist.