Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

Abstract

The sigma-1 receptor is a 223 amino acid-long protein with a recently identified structure. The sigma-2 receptor is a genetically unrelated protein with a similarly shaped binding pocket and acts to influence cellular activities similar to the sigma-1 receptor. Both proteins are highly expressed in neuronal tissues. As such, they have become targets for treating neurological diseases, including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple sclerosis (MS), Rett syndrome (RS), developmental and epileptic encephalopathies (DEE), and motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). In recent years, there have been many pre-clinical and clinical studies of sigma receptor (1 and 2) ligands for treating neurological disease. Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. Furthermore, several sigma-2 receptor ligands are under investigation, including CT1812, rivastigmine and SAS0132. This review aims to provide a current and up-to-date analysis of the current clinical and pre-clinical data of drugs with sigma receptor activities for treating neurological disease.

The Sigma Receptors in Alzheimer’s Disease: New Potential Targets for Diagnosis and Therapy

“…Many ligands targeting σ 1 and σ 2 receptors have been investigated for their therapeutic potential [46,49,50,[179][180][181][182][183][184][185]. Representative agents in clinical trials are provided in Figure 1 and Table 2.…”

“…Representative agents in clinical trials are provided in Figure 1 and Table 2. The progress of these ligands has been covered in some recent reviews [50,185]. Here, we describe only the ligands with therapeutic potential for AD.…”

Molecular Imaging of Alzheimer’s Disease-Related Sigma-1 Receptor in the Brain via a Novel Ru-Mediated Aromatic 18F-deoxyfluorination Probe

“…20 By targeting both the sigma-1 receptor and muscarinic receptors, Blarcamesine has the potential to exert effects on multiple pathways involved in neurodegenerative diseases, including AD and PD. 21 The dual-target profile of σ 1 R/σ 2 R agonists/ antagonists presents an intriguing opportunity for the development of novel therapeutic agents with broad-ranging effects on various disease states. 22,23 Molecular imaging with positron emission tomography (PET) could provide us with extensive bioinformation on σ 1 R, such as the expression and distribution, in living subjects in health and pathologic conditions.…”

“…Therapeutically, Blarcamesine (ANAVEX2–73), acting as a σ 1 R agonist and a muscarinic receptor modulator, has been analyzed in a recent Phase IIa clinical of AD therapy . By targeting both the sigma-1 receptor and muscarinic receptors, Blarcamesine has the potential to exert effects on multiple pathways involved in neurodegenerative diseases, including AD and PD . The dual-target profile of σ 1 R/σ 2 R agonists/antagonists presents an intriguing opportunity for the development of novel therapeutic agents with broad-ranging effects on various disease states. , …”

Sigma-1 Receptor Inhibition Reduces Mechanical Allodynia and Modulate Neuroinflammation in Chronic Neuropathic Pain

“…σ1R is expressed in several cell types, including neurons and astrocytes, playing a crucial role in multiple cellular functions, such as calcium signalling, lipid metabolism, protein folding and intercellular communication [ 17 ]. σ2R is also expressed in the CNS and in peripheral organs, gaining significant attention due to its role in several cellular processes, such as cell growth, differentiation and proliferation [ 18 ]. Such a profile has been of particular interest in cancer research, but also in neuroprotection and regeneration, for its role on sphingolipid second messenger in cell proliferation [ 19 , 20 ].…”