Using sigma-ligands as part of a multi-receptor approach to target diseases of the brain

ABSTRACT

Introduction

The sigma receptors are found abundantly in the central nervous system and are targets for the treatment of various diseases, including Alzheimer’s (AD), Parkinson’s (PD), Huntington’s disease (HD), depression, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). However, for many of these diseases, other receptors and targets have been the focus of the most, such as acetylcholine esterase inhibitors in Alzheimer’s and dopamine replacement in Parkinson’s. The currently available drugs for these diseases have limited success resulting in the requirement of an alternative approach to their treatment.

Areas covered

In this review, we discuss the potential role of the sigma receptors and their ligands as part of a multi receptor approach in the treatment of the diseases mentioned above. The literature reviewed was obtained through searches in databases, including PubMed, Web of Science, Google Scholar, and Scopus.

Expert opinion

Given sigma receptor agonists provide neuroprotection along with other benefits such as potentiating the effects of other receptors, further development of multi-receptor targeting ligands, and or the development of multi-drug combinations to target multiple receptors may prove beneficial in the future treatment of degenerative diseases of the CNS, especially when coupled with better diagnostic techniques.

KEYWORDS:

• Parkinson’s disease
• Alzheimer’s disease
• multiple Sclerosis
• sigma receptors
• neurological disease
• multi-targeting drugs

Article highlights

• Sigma-1 receptor expression is decreased in the brains of Alzheimer’s patients

• Donepezil and acetylcholinesterase inhibitor, the leading Alzheimer’s compound for treating Alzheimer’s disease in over 50 countries, has affinities for multiple targets, including the sigma-1 receptor.

• ANAVEX2-73 and AF710B, which show mixed affinity for the sigma-1 receptor and muscarinic receptors, are currently in clinical trials for Alzheimer’s disease.

• Pridopidine with an affinity for the sigma-1 receptor has shown promising results in clinical trials for the treatment of Huntington’s disease and has shown potential in animal models of Parkinson’s, and ALS.

• For the treatment of multiple sclerosis, NMDA antagonist, and sigma-1 receptor agonist eliprodil, has been shown to increase myelination 2-fold.

• NMDA antagonist, μ-opioid receptor agonist, and sigma-1 receptor agonist, dextromethorphan, increased OL and OL progenitor’s growth and differentiation

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

Dr. James M. Brimson was supported by the Rachadapisek Sompote Fund for Postdoctoral Fellowship, Chulalongkorn University.