Identification of dual Sigma1 receptor modulators/acetylcholinesterase inhibitors with antioxidant and neurotrophic properties, as neuroprotective agents

Setup and Validation of a Reliable Docking Protocol for the Development of Neuroprotective Agents by Targeting the Sigma-1 Receptor (S1R)

“…In particular, we selected compounds that exhibited different binding profiles to cover a wide range of K i values. Besides hit compounds emerged from our previous study ( 1 and 2 ) [ 15 ], we docked compounds 3 – 5 endowed with binding affinities lower than 10 nM, and compounds 6 , 7 which exhibited K i > 300 nM.…”

“…In fact, neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases as well as amyotrophic lateral sclerosis share common features, and these pathological cellular mechanisms develop in different ways, but all ultimately lead to apoptosis, necrosis, synapse and cell loss [ 1 , 3 , 14 ]. In our effort to discover new chemical entities against neurodegeneration, we recently disclosed two compounds as dual S1R modulators/acetylcholinesterase (AChE) inhibitors, characterized by the aryl-aminoalkyl-ketone structure reported in Figure 1 [ 15 ]. These compounds belong to a series of Multi Target Directed Ligands (MTDL) designed by combining the pharmacophoric elements of compound RC-33, the well-known AChE inhibitor Donepezil, and the antioxidant natural product Curcumin [ 15 ].…”

“…In our effort to discover new chemical entities against neurodegeneration, we recently disclosed two compounds as dual S1R modulators/acetylcholinesterase (AChE) inhibitors, characterized by the aryl-aminoalkyl-ketone structure reported in Figure 1 [ 15 ]. These compounds belong to a series of Multi Target Directed Ligands (MTDL) designed by combining the pharmacophoric elements of compound RC-33, the well-known AChE inhibitor Donepezil, and the antioxidant natural product Curcumin [ 15 ]. In particular, RC-33 is an in-house developed S1R agonist showing a nanomolar affinity against S1R and Sigma-2 receptor (S2R) ( K i S1R = 1.8 ± 0.1 nM; K i S2R = 45 ± 16 nM) , a good selectivity over S2R, μ-, and κ-opioid receptors, a high metabolic stability in several biological matrices and a suitable pharmacokinetic profile and Central Nervous System (CNS) distribution for in vivo administration.…”

“…In particular, RC-33 is an in-house developed S1R agonist showing a nanomolar affinity against S1R and Sigma-2 receptor (S2R) ( K i S1R = 1.8 ± 0.1 nM; K i S2R = 45 ± 16 nM) , a good selectivity over S2R, μ-, and κ-opioid receptors, a high metabolic stability in several biological matrices and a suitable pharmacokinetic profile and Central Nervous System (CNS) distribution for in vivo administration. In addition, RC-33 promotes the neurite differentiation and elongation in rat dorsal root ganglia (DRG) experimental model [ 15 ].…”

Novel Dual Ligands Targeting Sigma1 Receptor and Acetylcholinesterase Endowed with Antioxidant Properties

“…The new compounds series is characterized by a arylalkylaminoketone scaffold, which bears the structural elements of our developed S1R agonist RC-33, the well-known AChE inhibitor Donepezil and the antioxidant molecule Curcumin. Their affinity and selectivity towards S1R, their inhibition of AChE and their antioxidant profile were determined [1][2][3]. In the present communication we present the structure optimization of hit compounds, with the final aim to achieve viable tools for the treatment of neurodegenerative pathologies.…”