Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders

Abstract

Introduction: The sigma-1 receptor (S1R) is attracting much attention as a target for diseasemodifying therapies in neurodegenerative diseases. It is a highly conserved protein, present in plasma and endoplasmic reticulum (ER) membranes and enriched in mitochondria-associated ER membranes (MAMs). It modulates ER-mitochondria Ca 2+ transfer and activation of the ER stress pathways. Mitochondrial and MAM dysfunctions contribute to neurodegenerative processes in pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease or Amyotrophic Lateral Sclerosis. Interestingly, the S1R can be activated by small druggable molecules and accumulating preclinical data suggest that S1R agonists are effective protectants in these neurodegenerative diseases. Area covered: In this review, we will present the data showing the high therapeutic potential of S1R drugs for the treatment of neurodegenerative diseases, focusing on pridopidine as a potent and selective S1R agonist under clinical development. Of particular interest is the biphasic (bell-shaped) dose-response effect, representing a common feature of all S1R agonists and described in numerous preclinical models in vitro, in vivo and in clinical trials. Expert opinion: S1R agonists modulate essential inter-organelles communication altered in all neurodegenerative diseases and activate numerous intracellular survival pathways. Research in the field will continue growing in the near future. The particular cellular nature of this unique chaperone protein must be better understood to facilitate the developement of promising molecules at the clinical stage.

Pridopidine for the Improvement of Motor Function in Patients With Huntington's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…Second, pridopidine is a sigma-1 receptor (S1R) agonist, and the affinity of pridopidine for S1R is more than 100-fold higher than that for D2R ( 31 , 32 ). It exerts a neuroprotective effect by increasing BDNF expression and regulating PI3/AKT kinase signaling ( 33 , 34 ). Another approach was pridopidine interaction with S1R and activation of the SGK1 gene involved in the corticosteroid pathway to reduce neuronal sensitivity to toxic mHtt protein ( 35 , 36 ).…”

Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

“…Blarcamesine is currently being evaluated for AD, Rett syndrome, and PD dementia patients (NCT04314934, NCT04304482, NCT04575259). Results of completed clinical trials of S1R agonists in variety of disorders have been comprehensively summarized in recent reviews [4,130].…”

“…The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane protein residing in the endoplasmic reticulum (ER) [1][2][3]. S1R attracts significant attention as a potential drug target for treating neurological disorders [2,[4][5][6] and cancers [6].…”

Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant 18F-Labelled σ2 Receptor Ligand

“…Differences in the stereoselectivity, pharmacology, and molecular weight of guinea pig brain σ receptors and the binding sites of σ receptor ligands in PC12 cells, a tumor cell line derived from rat adrenal chromaffin cells, led to the designation of σ 1 and σ 2 receptors, respectively [ 2 ]. By contrast to the structurally and functionally thoroughly investigated and well described σ 1 receptor (for recent reviews of structure, function, and therapeutic potential, see, e.g., Tangui [ 3 ] or Soriani and Kourrich [ 4 ]), a profound characterization of the biology and a comprehensive understanding of the therapeutic potential of the σ 2 receptor were delayed mainly due to the absent identification of the protein and the coding gene. A significant step forward was the identification of progesterone receptor membrane component 1 (PGRMC1) as part of the protein complex containing the binding site of σ 2 receptor ligands, which was developed by Mach and colleagues in 2011 [ 5 ].…”

“…2-[4-(4-Fluoro-1H-indol-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (34, 72% yield). 1 H NMR (400 MHz, Chloroform-d) δ (ppm) = 7.18-7.02 (m, 3H),6.75 (ddd, J = 10.4, 7.0, 1.5 Hz, 1H), 6.58 (s, 1H),6.56 (dd, J = 3.2, 0.7 Hz, 1H), 6.48 (s, 1H), 4.20-4.11 (m, 2H),3.83 (s, 3H), 3.82 (s, 3H), 3.47 (s, 2H), 2.78 (t, J = 5.9 Hz, 2H), 2.64 (t, J = 5.7 Hz, 2H), 2.53-2.45 (m, 2H), 2.00-1.85 (m, 2H), 1.67-1.52 (m, 2H) 13. C NMR (100 MHz, Chloroform-d) δ (ppm) = 158.13, 154.86, 147.35 (d, J = 24.2 Hz), 138.69 (d, J = 11.5 Hz), 127.69, 126.29 (d, J = 26.6 Hz), 121.79 (d, J = 7.9 Hz), 117.55 (d, J = 22.5 Hz), 111.35, 109.46, 105.55 (d, J = 3.5 Hz), 104.05, 103.80, 97.08, 57.55, 55.91 (2C), 55.68, 50.99, 46.60, 28.62, 28.05, 24.51.…”