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.
Highlights
The most exploited paradigm in medicinal chemistry is the “one-target, one-disease”, according to which ligands are developed to act toward a single target in order to exert a beneficial effect
SA4503: a highly selective agonist proved to exert effects on memory, depression, cardiac hypertrophy, and hearing [48,49,50,51,52]; PB190: a selective agonist that showed neuroprotective and antidepressant activities [53,54,55]; PRE-084: a selective agonist with beneficial effects on learning impairment [56,57,58]; NE-100: a σ1 reference antagonist often used to counteract the action of claimed σ1 agonists [59,60]; PB212: a subnanomolar affinity and selective σ1 antagonist [53,61]; AC915: a highly selective ligand with an antagonist profile [62]; Pridopidine: initially considered a dopaminergic D2 receptor antagonist, it was later repositioned as a selective σ1 receptor agonist [63]; FTC-146: the ligand with the highest affinity and selectivity for σ1 receptor
Deeper studies able to clarify the mechanism of the σ1 receptors-mediated antineurodegenerative activity of NGP1-01 are not available, to the best of our knowledge, but the affinity of the compound for the σ1 receptor and the antineurodegenerative properties mediated by the reduction of Ca2+ influx have been demonstrated, qualifying NGP1-01 as a potential multi-targeted directed ligand (MTDL) that is useful in the treatment of neurodegenerative pathologies
Summary
The most exploited paradigm in medicinal chemistry is the “one-target, one-disease”, according to which ligands are developed to act toward a single target in order to exert a beneficial effect. SA4503: a highly selective agonist proved to exert effects on memory, depression, cardiac hypertrophy, and hearing [48,49,50,51,52]; PB190: a selective agonist that showed neuroprotective and antidepressant activities [53,54,55]; PRE-084: a selective agonist with beneficial effects on learning impairment [56,57,58]; NE-100: a σ1 reference antagonist often used to counteract the action of claimed σ1 agonists [59,60]; PB212: a subnanomolar affinity and selective σ1 antagonist [53,61]; AC915: a highly selective ligand with an antagonist profile [62]; Pridopidine: initially considered a dopaminergic D2 receptor antagonist, it was later repositioned as a selective σ1 receptor agonist (see Section 3.5) [63]; FTC-146: the ligand with the highest affinity and selectivity for σ1 receptor It has been radiofluorinated and employed in Positron Emission Tomography (PET) in mice, rats, squirrels, monkeys, and humans [64,65,66]; S1RA: a σ1 receptor antagonist developed by Esteve company for the treatment of neuropathic pain and the strengthening of opioid analgesia, which successfully completed Phase I clinical trial showing safety and tolerability [67,68]; BD1063: a σ1 receptor antagonist with anti-cocaine effects in mice [69,70]. In addition to the direct neuroprotective action of σ1 receptors, the additional modulation of targets such as opioid, N-methyl-D-aspartate (NMDA), dopaminergic, and cholinergic receptors renders the σ1 protein an intriguing target for the modulation of processes that involve these systems, prompting the development of σ1 -based MTDLs for the treatment of complex and multifactorial pathologies such as AD
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