Substituted benzo[d]oxazol-2(3H)-one derivatives with preference for the σ1 binding site

We describe here the synthesis and the binding interaction with σ1 and σ2 receptors of a series of new benzo[d]oxazol-2(3H)-one derivatives variously substituted on the N-benzyl moiety. The results of binding studies confirm the notion that the benzoxazolone moiety confers preference towards σ1 sites and establish that the ability to bind to σ1, but not to σ2 receptors, is strongly affected by the kind and the position of the substituents introduced in the N-benzyl ring. In fact, compounds with substitutions in para-position with atoms of Cl, H or F or with a CH3 group exhibit a higher affinity for σ1 receptors than the corresponding ortho-substituted compounds. The highest affinity and selectivity, with Ki values of 0.1 and 427 nM for σ1 and σ2 receptors, respectively, and a corresponding Kiσ2/Kiσ1 selectivity ratio of 4270 were found for the Cl-substituted compound.These results indicate that benzo[d]oxazol-2(3H)-one derivatives are among the most selective and σ1 receptor-preferring ligands currently available.

A series of substituted benzo[d]oxazol-2(3H)-one derivatives has been synthesized as a structural modification of indole derivatives previously described by us and the evaluation of their affinity towards σ1 and σ2 receptors was performed by radioligand binding assay.The highest s1 binding affinity was reached by the 4-chloro substituted benzoxazolone derivative, whose Kiσ1 value was 0.1 nM, with a Kiσ2/Kiσ1 selectivity ratio of 4270.Figure optionsDownload as PowerPoint slide