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 s1 and s2 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 s1 sites and establish that the ability to bind to s1, but not to s2 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 s1 receptors than the corresponding ortho-substituted compounds. The highest affinity and selectivity, with Ki values of 0.1 and 427 nM for s1 and s2 receptors, respectively, and a corresponding Kis2/Kis1 selectivity ratio of 4270 were found for the Cl substituted compound. These results indicate that benzo[d]oxazol-2(3H)-one are among the most selective and s1 receptor