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Papers of the Week

2019 Jul 15

Eur J Med Chem


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


Romeo G, Prezzavento O, Intagliata S, Pittalà V, Modica MN, Marrazzo A, Turnaturi R, Parenti C, Chiechio S, Arena E, Campisi A, Sposito G, Salerno L
Eur J Med Chem. 2019 Jul 15; 174:226-235.
PMID: 31042618.


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 σ and σ 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 values (K σ = 1.27, 2.30, and 0.78 and K σ = 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 σ receptor activity, while an in vivo mice model of inflammatory pain allowed to analyze σ receptor pharmacological properties. In vitro and in vivo results suggested that compound 19 is a σ/σ agonist, compound 24 a σ antagonist/σ agonist, whereas compound 22 might act as σ antagonist/σ partial agonist. Due to their pharmacological profile, a potential therapeutic application in cancer of aforesaid novel σ/σ receptor ligands, especially 22 and 24, is proposed.