Substituted benzo[d]oxazol-2(3H)-one derivatives with preference for the sigma1 binding site.
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.
Zampieri
Daniele
D
Department of Pharmaceutical Sciences, University of Trieste, P.le Europa 1, 34127 Trieste, Italy.
Grazia Mamolo
Maria
M
Laurini
Erik
E
Zanette
Caterina
C
Florio
Chiara
C
Collina
Simona
S
Rossi
Daniela
D
Azzolina
Ornella
O
Vio
Luciano
L
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
D001583:Benzoxazoles; D008024:Ligands; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C106107:sigma-2 receptor; C017057:benzoxazolone