Substituted benzo[d]oxazol-2(3H)-one derivatives with preference for the sigma1 binding site

Abstract: We describe here the synthesis and the binding interaction with sigma1 and sigma2 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 sigma1 sites and establish that the ability to bind to sigma1, but not to sigma2 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 sigma1 receptors than the corresponding ortho-substituted compounds. The highest affinity and selectivity, with Ki values of 0.1 and 427 nM for sigma1 and sigma2 receptors, respectively, and a corresponding Kisigma2/Kisigma1 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 sigma1 receptor-preferring ligands currently available.