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Review
.2023 May;37(5):399-440.
doi: 10.1007/s40263-023-01007-6. Epub 2023 May 11.

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

Affiliations
Review

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

Dicson S Malar et al. CNS Drugs.2023 May.

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.

© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Structure of the Xenopus sigma-1 receptor homotrimer (left) bound to (+)-pentazocine (ligand removed from image) and the Bovine sigma-2 receptor homodimer (right) bound to PB28, (ligand removed from image) at the membrane of the endoplasmic reticulum.
Fig. 2
Fig. 2
Chemical structures of drugs with sigma receptor activity discussed within this manuscript.
Fig. 3
Fig. 3
Some of the documented roles of the sigma-1 receptor in preventing neurological disease. (1) Activation of the sigma-1 receptor by an agonist result in the disassociation from binding immunoglobulin protein (BiP) and chaperoning of calcium channels at the mitochondria-associated ER membrane (MAM), resulting in calcium shuttling into the mitochondria and increased ATP production. (2) NMDA receptors are upregulated on sigma-1 activation and trafficked to the plasma membrane, and the sigma-1 receptor modulates NMDA receptor synaptic transmission and plasticity via SK channels. (3) Sigma-1 activation down-regulates calcium currents in L-type Ca2+ channels in retinal ganglion cells and upregulates calcium currents through L-type Ca2+ channels in the hippocampus. (4) Sigma-1 activation down-regulates Na+ currents through voltage-gated Na+ channels in intracardiac ganglion neurons. (5) Sigma-1 activation upregulates potassium currents through A-type K+ channels in neurohypophysial terminals andXenopus oocytes. Parasympathetic intracardiac neurons CA1 field of hippocampus. Sigma-1 activation can upregulate human ether-a-go go K+ currents inXenopus oocytes.
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