Allosteric Modulators of Sigma-1 Receptor: A Review

Allosteric modulators of sigma-1 receptor (Sig1R) are described as compounds that can increase the activity of some Sig1R ligands that compete with (+)-pentazocine, one of the classic prototypical ligands that binds to the orthosteric Sig1R binding site. Sig1R is an endoplasmic reticulum membrane protein that, in addition to its promiscuous high-affinity ligand binding, has been shown to have chaperone activity. Different experimental approaches have been used to describe and validate the activity of allosteric modulators of Sig1R. Sig1R-modulatory activity was first found for phenytoin, an anticonvulsant drug that primarily acts by blocking the voltage-gated sodium channels. Accumulating evidence suggests that allosteric Sig1R modulators affect processes involved in the pathophysiology of depression, memory and cognition disorders as well as convulsions. This review will focus on the description of selective and non-selective allosteric modulators of Sig1R, including molecular structure properties and pharmacological activity both in vitro and in vivo, with the aim of providing the latest overview from compound discovery approaches to eventual clinical applications. In this review, the possible mechanisms of action will be discussed, and future challenges in the development of novel compounds will be addressed

Dual-Acting Small Molecules: Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer's Disease Mouse Model.

We present the synthesis and characterization of merged human butyrylcholinesterase (hBChE) inhibitor/cannabinoid receptor 2 (hCB2R) ligands for the treatment of neurodegeneration. In total, 15 benzimidazole carbamates were synthesized and tested for their inhibition of human cholinesterases, also with regard to their pseudoirreversible binding mode and affinity toward both cannabinoid receptors in radioligand binding studies. After evaluation in a calcium mobilization assay as well as a β-arrestin 2 (βarr2) recruitment assay, two compounds with balanced activities on both targets were tested for their immunomodulatory effect on microglia activation and regarding their pharmacokinetic properties and blood-brain barrier penetration. Compound 15d, containing a dimethyl carbamate motif, was further evaluated in vivo, showing prevention of Aβ25-35-induced learning impairments in a pharmacological mouse model of Alzheimer's disease for both short- and long-term memory responses. Additional combination studies proved a synergic effect of BChE inhibition and CB2R activation in vivo

Etude pharmacologique in vivo des cibles moleculaires de la Phencyclidine (PCP) dans le systeme nerveux central de la souris

SIGLEINIST T 77371 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

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

International audienceIntroduction: 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

Mise en évidence d'une composante sigma-1 ( 1) dans les effets pharmacologiques et neuroprotecteurs du donepezil (aricept®) chez la souris

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Assessment of Topographic Memory in Mice in a Complex Environment Using the Hamlet Test

International audienc

Implication du récepteur sigma-1 dans les propriétés appétentes de la cocaïne (Intéraction avec les stéroïdes neuroactifs)

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

The Intriguing Sigma-1 and Sigma-2 Receptors and Their Potential Therapeutic Roles 2.0

: For some time now, the research on sigma receptors has been at a high level of maturity but, despite everything that has already been achieved, further work in this field still holds huge appeal, with vast possibilities for original discoveries [...]