Multi-Target Directed Ligands (MTDLs) Binding the σ1 Receptor as Promising Therapeutics: State of the Art and Perspectives

Abstract

The sigma-1 (σ1) receptor is a ‘pluripotent chaperone’ protein mainly expressed at the mitochondria–endoplasmic reticulum membrane interfaces where it interacts with several client proteins. This feature renders the σ1 receptor an ideal target for the development of multifunctional ligands, whose benefits are now recognized because several pathologies are multifactorial. Indeed, the current therapeutic regimens are based on the administration of different classes of drugs in order to counteract the diverse unbalanced physiological pathways associated with the pathology. Thus, the multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions, may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. This review aims to point out the progress in the development of MTDLs directed toward σ1 receptors for the treatment of central nervous system (CNS) and cancer diseases, with a focus on the perspectives that are proper for this strategy. The evidence that some drugs in clinical use unintentionally bind the σ1 protein (as off-target) provides a proof of concept of the potential of this strategy, and it strongly supports the promise that the σ1 receptor holds as a target to be hit in the context of MTDLs for the therapy of multifactorial pathologies.

SK2 channels set a signalling hub bolstering CAF-triggered tumourigenic processes in pancreatic cancer

“…More importantly, pharmacological inhibition of Sig-1R was efficient in vivo as mouse models of PDAC treated with 1(S) dramatically delayed tumour development, reduced metastasis onset and extended survival. Although stromal ablation for PDAC treatment remains controversial, our results suggest a potential therapeutic opportunity by targeting an ion channel-dependent signalling hub through its regulator, Sig-1R, a druggable ion channel chaperone,9 46 to reduce stromal-induced PDAC aggressiveness (figure 8). Because Sig-1R activity is stimulated by stress in diseased tissues,47 the use of Sig-1R ligands should specifically target SK2 in tumours but not in brain or heart.…”

Multitargeting nature of muscarinic orthosteric agonists and antagonists

“…This type of drug action is not specific to mAChRs but is, at least in some cases, an advantage of drugs, allowing them to affect more pathway changes in specific diseases ( Abatematteo et al, 2021 ). Surprisingly, we can find that ligands believed to specifically bind to one neurotransmitter receptor type had much wider activities.…”

“…Additionally, it is necessary to stress that multitarget drug interactions can be considered an advantage in drug effects, as they allow drugs to target more receptors and thus activate more signaling pathways (typically involving sigma receptors) ( Maurice and Su, 2009 ; Abatematteo et al, 2021 ), which can decrease the required dose of a given drug and produce additive effects with the use of one drug.…”

The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology

“…DMT can also regulate the activity of ionotropic NMDA receptors directly, by modulating memory and learning processes, or indirectly, by activating the sigma-1 receptor [ 129 , 130 , 131 , 132 ]. The sigma-1 receptor is a chaperonin localized in the endoplasmic reticulum of cells of the cerebral or peripheral tissues [ 133 ]. Given the widespread distribution of the sigma-1 receptor, it has been studied in various diseases and neurobiological conditions such as addiction, depression, amnesia, pain, stroke and cancer [ 133 ].…”

“…The sigma-1 receptor is a chaperonin localized in the endoplasmic reticulum of cells of the cerebral or peripheral tissues [ 133 ]. Given the widespread distribution of the sigma-1 receptor, it has been studied in various diseases and neurobiological conditions such as addiction, depression, amnesia, pain, stroke and cancer [ 133 ]. DMT binds to the sigma-1 receptor at micromolar concentrations, contributing to the psychedelic response [ 130 , 132 ].…”