Residence Time (RT), a new parameter to predict neurosteroidogenic efficacy of Translocator Protein (TSPO) ligands: N,N-dialkyl-2-arylindol-3-ylglyoxylamides, a case study

Targeting neuroactive steroid biosynthetic pathway by specific 18 kDa Translocator Protein (TSPO) ligands may represent a therapeutic approach in a variety of neurodegenerative and neuropsychiatric diseases. However, the lack of correlation between the binding affinity and the in vitro steroidogenic efficacy has limited the identification of lead compounds by a traditional affinity-based drug discovery strategy. Our recent researches indicate that the key factor for robust steroidogenic TSPO ligand efficacy is not the binding affinity per se, but rather the time the compound spends into the target, namely its Residence Time (RT). The assessment of this kinetic parameter during the in vitro characterization of compounds appears mandatory in order to obtain structure-efficacy relationships suitable for the future development of novel molecules with promising pharmacological properties.