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Additional file 1: Figure S1. A 2D-SIFt representation of the common binding site profile for the antagonists in G Protein-Coupled Receptors. The intensity of gray corresponds to the number of feature-receptor interactions. Table S1. Crystal structures used for the construction of the common antagonist binding site for Class A GPCRs. Table S2. Crystal structures used for the comparison of the agonist and antagonist binding modes for β2AR. Table S3. Individual 2D-SIFt heat maps for the crystal structures used for construction of the common binding site of the GPCR antagonists.

The complex etiology of Alzheimer’s disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT6 receptor (5-HT6R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HT6R with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT6R at Gs signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT6R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.