Synthesis, in vitro and in vivo characterization of new benzoxazole and benzothiazole-based sigma receptor ligands

A new set of 5-chlorobenzoxazole- and 5-chlorobenzothiazole-based derivatives containing the azepane ring as a basic moiety was designed, synthesized and evaluated through binding assays to measure their affinity and selectivity towards sigma(1) and sigma(2) receptors. Compounds 19, 22 and 24, with a four units spacer between the bicyclic scaffold and the azepane ring, showed nanomolar affinity towards both receptor subtype and the best K-i values (K-i sigma(1)=1.27, 2.30, and 0.78 and K-i sigma(2) = 7.9, 3.8, and 7.61 nM, respectively). Evaluation of cytotoxic and apoptotic effects in MCF-7 human cancer cells was useful to assess sigma(2) receptor activity, while an in vivo mice model of inflammatory pain allowed to analyze sigma(1) receptor pharmacological properties. In vitro and in vivo results suggested that compound 19 is a sigma(1)/sigma(2) agonist, compound 24 a sigma(1) antagonist/sigma(2) agonist, whereas compound 22 might act as sigma(1) antagonist/sigma(2) partial agonist. Due to their pharmacological profile, a potential therapeutic application in cancer of aforesaid novel sigma(1)/sigma(2) receptor ligands, especially 22 and 24, is proposed. (C) 2019 Elsevier Masson SAS. All rights reserved.