Recent Advances in the Development of Sigma-1 Receptor Ligands

Abstract

The existence of two distinct sigma (s) receptor subtypes was established in the early 1990s. Sigma-1 and sigma-2 receptors (S1Rs and S2Rs, respectively) were shown to possess distinct molecular size, anatomical distribution, and ligand discrimination. S2R is overexpressed in numerous human cancers, and has therapeutic potential for the imaging and treatment of certain tumours. In contrast, S1R is more broadly involved in a wide variety of central nervous system (CNS) diseases including motor disorders, memory deficits, depression, schizophrenia, anxiety, pain, drug addiction, and many more. Since the human S1R was cloned in 1996, numerous high affinity ligands with excellent selectivity for S1R have been developed. This review focuses on recent developments in the generation of structurally diverse S1R-selective ligands and novel therapeutic candidates targeting S1Rs. include medicinal chemistry, heterocyclic chemistry, drug discovery, and structure-activity relationships of molecules with activity in the central nervous system. He serves on several journal editorial boards focussing on medicinal chemistry, pharmaceutical design and drug discovery.

Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases

“…Several diversified core scaffolds have been identified in σ 1 receptor ligands so far and there appears to be no generally accepted system for classification of such molecules. In 2015, Kassiou and co-workers 125 produced a valuable summary on the development of σ 1 receptor ligands up to the year 2014. Thus, this review relies on broad structural similarity and provides a summation of recent advances in σ 1 receptor orthosteric ligand discovery and development since 2014.…”

A systematic exploration of the effects of flexibility and basicity on sigma (σ) receptor binding in a series of substituted diamines

“…7 Consequently, S1Rs are involved in numerous neurological disorders including depression, anxiety, substance abuse, schizophrenia, psychosis, memory deficit disorders (such as dementia and Alzheimer's disease), and motor disorders (including Parkinson's disease). 9,10 The S1R has also experienced a recent surge of interest due to its involvement in analgesia, 11,12 with a noteworthy ligand (E-52862) progressing to Phase II clinical trials for the treatment of pain. 13 Due to the high expression of S2R in malignant tumours, S2R ligands have been utilised diagnostically for radiolabelling tumour sites, and have also been investigated therapeutically for their ability to induce apoptosis in cancer cells.…”

“…17 Preceding this discovery, ligand design was propelled by pharmacophore refinements. A myriad of functional S1R ligands have now been identified, 12 and common features for binding have been elucidated. [18][19][20] Glennon and co-workers identified the ideal distance between a basic amine and two tethered hydrophobic groups (named primary and secondary hydrophobic regions) for prototypic aminergic S1R ligands.…”

Norbenzomorphan Scaffold: Chemical Tool for Modulating Sigma Receptor-Subtype Selectivity

“…6 This receptor is involved in regulation of K + and Ca 2+ levels, as well as modulation of neuronal firing and neurotransmitter release. A multitude of ligands are known that bind to the σ1 receptor, 7 and several drug candidates that bind to σ1 receptors are in clinical trials for Alzheimer's disease (AD), 8 epilepsy, 6 and pain. 9 Moreover, drugs such as donepezil, fluvoxamine, 10 and opipramol 11 have high affinity for the σ1 receptor and are in current use.…”