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

Abstract

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 σ₁/σ₂ 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 σ₁/σ₂ affinity. 6-(3-(Azepan-1-yl)propoxy)-4H-chromen-4-one (20) showed a K_i value for σ₁ of 27.2 nM (selectivity (σ₁/σ₂) = 28), combining the desired σ₁ 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 σ₁ receptor antagonist.