In this study novel ligands of the translocator protein (TSPO), characterized by a five-membered aromatic heterocycle (i.e. oxazole, isoxazole, oxadiazole), a phenyl ring, and an amide side chain of carboxy or acetic type, were designed using a previously reported pharmacophore/topological model. Most of compounds showed significant TSPO binding affinity (K i values in the nanomolar/submicromolar range), the highest being displayed by oxazolacetamides 6. A number of compounds were tested for their ability to inhibit the proliferation/viability of human glioblastoma cell line U87MG. The dose-time dependent cell response to treatment with 6d demonstrated the specificity of the observed effect. The ability of 6d to induce mitochondrial membrane dissipation (ΔΨm) substantiates the intracellular pro-apoptotic mechanism activated by ligand binding to TSPO.

Tertiary amides with a five-membered heteroaromatic ring as new probes for the translocator protein

SIMORINI, FRANCESCA;TALIANI, SABRINA;LA MOTTA, CONCETTINA;DA SETTIMO PASSETTI, FEDERICO;COSTA, BARBARA;DA POZZO, ELEONORA;MARTINI, CLAUDIA
2011

Abstract

In this study novel ligands of the translocator protein (TSPO), characterized by a five-membered aromatic heterocycle (i.e. oxazole, isoxazole, oxadiazole), a phenyl ring, and an amide side chain of carboxy or acetic type, were designed using a previously reported pharmacophore/topological model. Most of compounds showed significant TSPO binding affinity (K i values in the nanomolar/submicromolar range), the highest being displayed by oxazolacetamides 6. A number of compounds were tested for their ability to inhibit the proliferation/viability of human glioblastoma cell line U87MG. The dose-time dependent cell response to treatment with 6d demonstrated the specificity of the observed effect. The ability of 6d to induce mitochondrial membrane dissipation (ΔΨm) substantiates the intracellular pro-apoptotic mechanism activated by ligand binding to TSPO.
Cosimelli, B; Simorini, Francesca; Taliani, Sabrina; LA MOTTA, Concettina; DA SETTIMO PASSETTI, Federico; Severi, E; Greco, G; Novellino, E; Costa, Barbara; DA POZZO, Eleonora; Bendinelli, S; Martini, Claudia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/189339
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