The effects of sigma ligands on protein release from lacrimal acinar cells: a potential agonist/antagonist assay

Schoenwald, Ronald D.; Barfknecht, Charles F.; Shirolkar, Satish V.; Xia, Erning

doi:10.1016/0024-3205(95)00073-9

Cited by 10 publications

(11 citation statements)

References 13 publications

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“…Furthermore, the underlying molecular mechanistic differences between agonists and antagonists have not been well characterized across different pathological contexts (Katz et al, 2016; Merlos et al, 2017), and it must be noted that some of the observations and interpretations are not monolithic (Katz et al, 2017). For example, the σ 1 R ligand BMY 14802 was characterized as both an antagonist and an agonist (Schoenwald et al, 1995; Taylor et al, 1993). This discrepancy can be attributed to readouts and interpretations at different downstream effector levels.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays

Yano

Bonifazi

et al. 2018

Neuropharmacology

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The sigma 1 receptor (σR) is a structurally unique transmembrane protein that functions as a molecular chaperone in the endoplasmic reticulum (ER), and has been implicated in cancer, neuropathic pain, and psychostimulant abuse. Despite physiological and pharmacological significance, mechanistic underpinnings of structure-function relationships of σR are poorly understood, and molecular interactions of selective ligands with σR have not been elucidated. The recent crystallographic determination of σR as a homo-trimer provides the foundation for mechanistic elucidation at the molecular level. Here we report novel bioluminescence resonance energy transfer (BRET) assays that enable analyses of ligand-induced multimerization of σR and its interaction with BiP. Haloperidol, PD144418, and 4-PPBP enhanced σR homomer BRET signals in a dose dependent manner, suggesting their significant effects in stabilizing σR multimerization, whereas (+)-pentazocine and several other ligands do not. In non-denaturing gels, (+)-pentazocine significantly decreased whereas haloperidol increased the fraction of σR multimers, consistent with the results from the homomer BRET assay. Further, BRET assays examining heteromeric σR-BiP interaction revealed that (+)-pentazocine and haloperidol induced opposite trends of signals. From molecular modeling and simulations of σR in complex with the tested ligands, we identified initial clues that may lead to the differed responses of σR upon binding of structurally diverse ligands. By combining multiple in vitro pharmacological and in silico molecular biophysical methods, we propose a novel integrative approach to analyze σR-ligand binding and its impact on interaction of σR with client proteins.

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Section: Introductionmentioning

confidence: 99%

Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays

Yano

Bonifazi

et al. 2018

Neuropharmacology

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“…Although the terms agonist and antagonist have been used to classify σ 1 receptor ligands, an unambiguous definition of the functional activity (agonist versus antagonist) is often hard. As a matter of fact, both agonists (i.e., fluvoxamine and other selective serotonin reuptake inhibitors (SSRIs) [30]) and antagonists (i.e., rimcazole [31,32]) are effective in treating some pathologies such as psychosis, and there are some ligands (i.e., BMY 14802 [33,34]) that show both agonist and antagonist activities in different conditions [35].…”

Section: σ1mentioning

confidence: 99%

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

Abatematteo

Niso

Contino

et al. 2021

IJMS

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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.

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“…σ binding sites seem to be implicated in a wide variety of functions, ranging from the motor control to the synthesis and/or release of several neurotransmitters or cell proteins. [9][10][11][12][13] Recent observations suggest that σ binding sites may be also implicated in the cell growth and proliferation. 14,15 Although their physiological significance is not yet completely known, the potential involvement of σ sites in affective disorders and in schizophrenia has been suggested.…”

Section: Introductionmentioning

confidence: 99%

(+)-cis-N-Ethyleneamino-N-normetazocine Derivatives. Novel and Selective σ Ligands with Antagonist Properties

et al. 1998

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A series of (+)-cis-N-normetazocine derivatives has been described, and their affinities for sigma1, sigma2, and phencyclidine (PCP) sites and opioid, muscarinic (M2), dopamine (D2), and serotonin (5-HT2) receptors were evaluated. The effect of the N-substitution with a substituted ethylamino spacer was investigated. Compounds 8c-11c displayed high affinities for sigma1 sites and for opioid receptors. Substitution of the second basic nitrogen either with alkyl or cycloalkyl substituents give compounds (1a-6a) with high affinity and selectivity for sigma1 binding sites. Compounds 1a-5a were further characterized in vivo, and their agonist/antagonist activity was evaluated. In mouse, compound 1a and 2a as well as haloperidol suppressed in a dose-related manner the stereotyped behavior induced by (+)-SKF 10,047. Compounds 3a-5a and (+)-pentazocine do not affect the stereotyped behavior induced by ip injection of (+)-SKF 10,047. Therefore, from this series of compounds we identified potent and selective sigma1 ligands which might prove useful to unveil the functional role of sigma1 sites.

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The effects of sigma ligands on protein release from lacrimal acinar cells: a potential agonist/antagonist assay

Cited by 10 publications

References 13 publications

Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays

Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays

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

(+)-cis-N-Ethyleneamino-N-normetazocine Derivatives. Novel and Selective σ Ligands with Antagonist Properties

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