title: 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 sigma(1) and sigma(2) 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 sigma(1) sites and establish that the ability to bind to sigma(1), but not to sigma(2) 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 CH(3) group exhibit a higher affinity for sigma(1) receptors than the corresponding ortho-substituted compounds. The highest affinity and selectivity, with K(i) values of 0.1 and 427 nM for sigma(1) and sigma(2) receptors, respectively, and a corresponding K(i)sigma(2)/K(i)sigma(1) 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 sigma(1) receptor-preferring ligands currently available.
authors.affiliation: Department of Pharmaceutical Sciences, University of Trieste, P.le Europa 1, 34127 Trieste, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Zampieri
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia Mamolo
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.forename: Caterina
authors.initials: C
authors.lastname: Zanette
authors.forename: Chiara
authors.initials: C
authors.lastname: Florio
authors.forename: Simona
authors.initials: S
authors.lastname: Collina
authors.forename: Daniela
authors.initials: D
authors.lastname: Rossi
authors.forename: Ornella
authors.initials: O
authors.lastname: Azzolina
authors.forename: Luciano
authors.initials: L
authors.lastname: Vio
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D008024:Ligands; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D001583:Benzoxazoles; D008024:Ligands; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C106107:sigma-2 receptor; C017057:benzoxazolone