Toward the Identification of Neuroprotective Agents: G-Scale Synthesis, Pharmacokinetic Evaluation and Cns Distribution of ( R )-Rc-33, a Promising Sigma1 Receptor Agonist

Abstract

(R)-RC-33 may be a promising candidate for in vivo studies in animal models of neurodegenerative diseases.

Structure–Activity Relationships within a Series of σ1 and σ2 Receptor Ligands: Identification of a σ2 Receptor Agonist (BS148) with Selective Toxicity against Metastatic Melanoma

“…[14,[17][18][19] High-affinity s 1 Rl igandsh ave been considered to play an important role in the treatment of various neurodegenerative disorders, including Parkinson's, Alzheimer's, and Huntington's diseases,d ementias, cognitive aging, depression, schizophrenia, neuropathicp ain, drug addiction, stroke, HIV infection, and cancer. [20][21][22][23][24][25][26][27][28][29] Unlike s 1 Rs, s 2 Rs are less understood and have not yet been cloned. Recently,t he progesterone receptor membrane component 1( PGRMC1) has been proposeda st he s 2 R binding site, [30] although this wasq uestioned by other evidence supporting that the two targets are two different proteins.…”

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.…”

Sigma 1 receptor modulators as a new weapon against multiple sclerosis

“…Nevertheless, they are suitable only for systemic administration and fairly expensive, hence academic and industrial environments are still addressing their efforts towards the development of new drugs Chamberlain et al (2016). Considering that neurodegeneration is a contributory factor in the onset of MS, Sigma 1 Receptor (S1R) could play a crucial role in MS , Peviani et al (2014).…”

“…During the years, our interdisciplinary research group identified compound (R)-RC-33, as a new selective S1R agonist with an excellent S1R affinity (Ki= 1.8 nM) along with high selectivity over other receptors, including S2R, and good in vitro metabolic stability Rossi et al (2010), , Marra et al (2016). On the bases of these results, (R)-RC-33 has been selected as lead compound for MS preliminary biological assay.…”

“…Nevertheless, they are suitable only for systemic administration and fairly expensive, hence academic and industrial environments are still addressing their efforts towards the development of new drugs Chamberlain et al (2016). Considering that neurodegeneration is a contributory factor in the onset of MS, Sigma 1 Receptor (S1R) could play a crucial role in MS , Peviani et al (2014).During the years, our interdisciplinary research group identified compound (R)-RC-33, as a new selective S1R agonist with an excellent S1R affinity (Ki= 1.8 nM) along with high selectivity over other receptors, including S2R, and good in vitro metabolic stability Rossi et al (2010), ), Marra et al (2016. On the bases of these results, (R)-RC-33 has been selected as lead compound for MS preliminary biological assay.…”