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Psychostimulant use disorders (PSUD) are prevalent; however, no FDA‐approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3‐24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine‐induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8‐091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine‐induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine. [ABSTRACT FROM AUTHOR]

The sigma-2 (σ2) receptor has been linked to several diseases and conditions including cancer, neuropathic drug addiction, Alzheimer's disease, Parkinson's disease, traumatic brain injury, Niemann-Pick disease, schizophrenia, depression, and anxiety. Targeting σ2 as a means of treating these diseases and conditions has been the subject of intense research, and several clinical trials have been launched to determine the real-world therapeutic utility of this target. Herein, we report the identification of a novel, semirigid series of functionalized 3,3-dialkyl-γ-butyrolactone σ2 ligands, containing piperazine bioisosteres. The compounds were evaluated using a variety of in vitro assays to determine affinity for sigma receptors, σ1/ σ2 selectivity profiles, aqueous solubility, and mouse liver microsome stability. [ABSTRACT FROM AUTHOR]

Sigma 1 receptor (Sig1R), a pluripotent modulator of cell survival, is neuroprotective in models of retinal degeneration when activated by the high-affinity, high-specificity ligand (+)-pentazocine ((+)-PTZ). The molecular mechanisms of Sig1R-mediated retinal neuroprotection are under investigation. We previously reported that the antioxidant regulatory transcription factor Nrf2 may be involved in Sig1R-mediated retinal photoreceptor cell (PRC) rescue. Cullin 3 (Cul3) is a component of the Nrf2-Keap1 antioxidant pathway and facilitates Nrf2 ubiquitination. Our earlier transcriptome analysis revealed decreased Cul3 in retinas lacking Sig1R. Here, we asked whether Sig1R activation can modulate Cul3 expression in 661 W cone PRCs. Proximity ligation and co-immunoprecipitation (co-IP) showed that Cul3 resides closely to and co-IPs with Sig1R. Activation of Sig1R using (+)-PTZ significantly increased Cul3 at the gene/protein level; silencing Sig1R decreased Cul3 gene/protein levels. Experiments in which Cul3 was silenced in cells exposed to tBHP resulted in increased oxidative stress, which was not attenuated with Sig1R activation by (+)-PTZ, whereas cells transfected with scrambled siRNA (and incubated with tBHP) responded to (+)-PTZ treatment by decreasing levels of oxidative stress. Assessment of mitochondrial respiration and glycolysis revealed significantly improved maximal respiration, spare capacity and glycolytic capacity in oxidatively-stressed cells transfected with scrambled siRNA and treated with (+)-PTZ, but not in (+)-PTZ treated, oxidatively-stressed cells in which Cul3 had been silenced. The data provide the first evidence that Sig1R co-localizes/interacts with Cul3, a key player in the Nrf2-Keap1 antioxidant pathway. The data suggest that the preservation of mitochondrial respiration/glycolytic function and reduction of oxidative stress observed upon activation of Sig1R occur in part in a Cul3-dependent manner. [Display omitted] • Sig1R activation and its relationship to Cul3 were assessed in photoreceptor cells. • Sig1R co-localizes/interacts with Cul3, a player in the Nrf2-Keap1 antioxidant pathway. • Sig1R activation increased, while silencing Sig1R decreased, Cul3 gene/protein levels. • Sig1R activation preserved mitochondrial/glycolytic function in a Cul3-dependent manner. • Activation of Sig1R reduced oxidative stress, which was Cul3 dependent. [ABSTRACT FROM AUTHOR]

Sigma receptor is a transmembrane non‐GPCR protein expressed mainly in the endoplasmic reticulum membrane associated with mitochondria. It is classified into two types: Sigma‐1 (S1R) and Sigma‐2 (S2R) based on their biological functions. S1R has been implicated in many neurological disorders such as anxiety, schizophrenia, and depression. Therefore, S1R ligands possess a variety of potential clinical applications with a great interest in the treatment of neuropathic pain. In this study, we report the discovery of a novel lead compound for S1R binding, based on the thiazolidine‐2,4‐dione nucleus. We have explored hydrophobic groups of different sizes on both sides of the five‐membered ring scaffold guided by the crystal structure of S1R. Six compounds showed more than 50% displacement of the radioligand at 10 µM concentration with compound 6c resulting in 100% displacement and a Ki of 95.5 nM. Moreover, compounds 6c and 6e showed a significant selectivity over S2R. In addition, molecular docking predicted that all the compounds showed the critical salt bridge with Glu172 with variable degrees of π‐stacking interaction with Tyr103. Upon optimization, this series of compounds could represent potential clinically useful S1R ligands for pain management. [ABSTRACT FROM AUTHOR]

The sigma-2 (σ2) receptor was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein)). This protein has been linked to diseases and conditions such as Niemann-Pick disease, schizophrenia, neuropathic pain, traumatic brain injury, cancer, drug addiction, and Alzheimer's disease. The therapeutic utility of σ2 ligands is under investigation in numerous laboratories and on-going clinical trials. Herein, we report the identification of a series of novel 5-(2-(5-arylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-γ-butyrolactone and their evaluation using in vitro σ2 and sigma-1 (σ1) assays to determine their σ1/σ2 selectivity profiles, as well as a series of in vitro ADME assays. [ABSTRACT FROM AUTHOR]

Aims: Preclinical studies of MR309, a selective sigma‐1 receptor (σ1R) antagonist, support a potential role in treating neuropathic pain. We report 2 studies that provide insight into the pharmacokinetics (PK) and brain σ1R binding of MR309. Methods: Steady‐state PK of MR309 (400 mg once daily and 200 mg twice‐daily [BID] for 10 days; EudraCT 2015–001818‐99 [PK study]) and the relationship between MR309 plasma exposure and brain σ1R occupancy (EudraCT 2017–000670‐11 [positron emission tomography study]) were investigated in healthy volunteers. Positron emission tomography using the σ1R ligand [11C]SA4503 was conducted at baseline, and 2 and 8 hours after a single dose of MR309 (200–800 mg). The relationship between brain σ1R occupancy and MR309 exposure was explored using data‐driven model fitting. Results: MR309 was well tolerated, brain σ1R occupancy ranged between 30.5 and 74.9% following single‐dose MR309 (n = 7). MR309 BID provided a plasma PK profile with less fluctuation than once daily dosing (n = 16). MR309 200 mg BID yielded average steady state plasma concentrations between 2000 and 4000 ng/mL in the PK study, which corresponded to an estimated brain σ1R occupancy of 59–74%. Conclusion: MR309 200 mg BID dose was below the 75% σ1R occupancy threshold expected to elicit maximal antinociceptive effect as observed in neuropathic pain models. Further investigations of MR309 for neuropathic pain will require higher brain σ1R occupancy, and establish the optimal dose by elucidating the clinical impact of a broad range of brain σ1R occupancy across different neuropathic pain indications. [ABSTRACT FROM AUTHOR]

The sigma-2 (σ2) receptor, also known as the Transmembrane Protein 97 (TMEM97, and MAC30 (Meningioma-associated protein), has been linked to a number of conditions are disease states such as schizophrenia, cancer, Alzheimer's disease, traumatic brain injury, and neuropathic pain. As part or our on-going effort identify novel σ2 ligands, we have identified a series of novel, functionalized oxazolidin-2-one sigma-2 ligands (4). Our lead compound (4h) demonstrated high affinity (Ki = 36 nM) and excellent σ1/σ2 selectivity (79-fold). Evaluation of its affinity at key CNS targets via the Psychoactive Drug Screening Program (PDSP) also indicated a high degree of selectivity for σ2 over other receptors. [ABSTRACT FROM AUTHOR]

The sigma-2 (σ2) receptor was discovered nearly 40 years ago and was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein)). Aberrant σ2 activity has been linked to diseases and conditions such as schizophrenia, Alzheimer's disease, neuropathic pain, traumatic brain injury, and cancer. The utility of σ2 as a therapeutic target is currently under investigation in numerous laboratories. Herein, we report on the synthesis and evaluation of a series of novel, functionalized γ-butyrolactones that are potent σ2 receptor ligands. [ABSTRACT FROM AUTHOR]

Since the first discovery of antipsychotics in the 1950s, targeting dopaminergic drugs has manifested to well manage the positive symptoms of schizophrenia with limited efficacy for the negative and cognitive symptoms. In past decades, extensive efforts have been undertaken towards the development of innovative agents that can effectively stabilize the dopamine and serotonin systems or target to nondopaminergic pathways, leading to various promising drug candidates entering into clinical trials. Notably, the sigma-2, 5-HT 2A , and α 1A receptor antagonist roluperidone, as well as a fixed-dose combination of the M 1/4 receptor agonist KarXT, have been submitted for NDA applications. The dual agonist ulotaront, which targets TAAR1 and 5-HT 1A receptors, and the GlyT1 inhibitor iclepertin have advanced into phase 3 clinical trials. Nevertheless, satisfactory therapeutic strategies for schizophrenia remain elusive. This review highlights current clinical endeavors in developing novel chemical small-molecule entities and fixed-dose combinations for the treatment of schizophrenia since 2017, thus facilitating the efficient development of the next generation of antipsychotics., (© 2024 Wiley Periodicals LLC.)

Ras‐related C3 botulinum toxin substrate 1 (Rac1), of the Rho small GTPase family, is a key regulator of actin cytoskeleton rearrangement and plays an important role in dendritic morphogenesis. Cocaine produces neuronal alterations, including structural changes in dendritic number and morphology. Emerging data indicate sigma‐1 receptors (σ‐1Rs) as a promising candidate for the prevention of cocaine craving. Opipramol is a σ‐1R agonist approved in some European countries for depression and anxiety. Here we report that opipramol, mediated by Rac1, attenuates cocaine‐seeking behavior in a rat model of self‐administration. The opipramol effect was shown in two phases. It decreased cocaine‐seeking behavior throughout the withdrawal phase and, interestingly, showed a significant reduction of cocaine‐primed reinstatement in 75% of the opipramol‐treated group (termed 'responders'). All opipramol‐treated rats showed a decrease in σ‐1R mRNA expression levels in the nucleus accumbens (NAc) versus controls. Responders also exhibited significantly decreased NAc Rac1 mRNA expression levels, compared with non‐responder rats. Hence, Rac1 differentiated responders from non‐responders. Rac1 correlated positively with σ‐1R mRNA levels in opipramol responders. In another experiment, Rac1 inhibitor injected directly into the NAc core decreased active lever presses on the first day of extinction, indicating the critical role of Rac1 in the opipramol effect on drug seeking. We postulate that chronic activation of σ‐1R, through a dynamic interaction with Rac1, may suggest a new approach to treat substance use disorder (SUD). Rac1 inhibition is a prerequisite for decreasing drug seeking and rehabilitation, and this can be achieved by opipramol, a medication that can be given during detoxification. [ABSTRACT FROM AUTHOR]

Nearly 40 years after the first disclosure of sigma receptors, the sigma-2 (σ2) receptor was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein). This macromolecule has been associated with a number of disease states such as schizophrenia, Alzheimer's disease, neuropathic pain, traumatic brain injury, and cancer. We have recently identified a series of novel, functionalized γ-butyrolactones that are potent σ2 receptor ligands that are drug-like and identified a potential candidate (9z) for future in vivo study. [ABSTRACT FROM AUTHOR]

Rationale: The N-phenylpropyl-N′-substituted piperazines SA-4503 (N-phenylpropyl-N′-(3,4-dimethoxyphenethyl)piperazine) and YZ-185 (N-phenylpropyl-N′-(3-methoxyphenethyl)piperazine) bind to sigma (σ) receptors and block the development of cocaine-induced conditioned place preference at concentrations that inhibit cocaine-induced hyperactivity. YZ-067 (N-phenylpropyl-N′-(4-methoxyphenethyl)piperazine) also binds to sigma receptors and attenuates cocaine-induced hyperactivity in mice. Objectives: The present study determined the effect of YZ-067 on the development and expression of cocaine (66 μmol/kg or 33 μmol/kg) conditioned place preference (CPP) and locomotor sensitization in mice. Results: YZ-067 (10 or 31.6 μmol/kg) did not have intrinsic effects on place preference or place aversion. Interestingly, the 31.6 μmol/kg YZ-067 dose enhanced the development of cocaine place preference, while 10 μmol/kg YZ-067 attenuated the development of cocaine-induced locomotor sensitization. However, YZ-067 did not alter the expression of cocaine place preference nor cocaine-induced locomotor sensitization. In follow-up studies, YZ-067 did not affect performance in the zero maze or rotarod, indicating that sigma receptors probed by this ligand do not regulate anxiety-like or coordinated motor skill behaviors, respectively. Conclusion: Overall, these results are consistent with previous studies demonstrating a role for sigma receptors in the behavioral effects of cocaine. However, the present findings also indicate that N-phenylpropyl-N′-substituted piperazines do not strictly block cocaine's behavioral effects and that sigma receptor may differentially mediate cocaine-induced hyperactivity and place conditioning. [ABSTRACT FROM AUTHOR]

Sigma 1 receptor (Sig1R), a modulator of cell survival, has emerged as a novel target for retinal degenerative disease. Studies have shown that activation of Sig1R, using the high affinity ligand (+)-pentazocine ((+)-PTZ), improves cone function in a severe retinopathy model. The rescue is accompanied by normalization of levels of NRF2, a key transcription factor that regulates the antioxidant response. The interaction of Sig1R with a number of proteins has been investigated; whether it interacts with NRF2, however, is not known. We used co-immunoprecipitation (co-IP), proximity ligation assay (PLA), and electron microscopy (EM) immunodetection methods to investigate this question in the 661W cone photoreceptor cell line. For co-IP experiments, immune complexes were precipitated by protein A/G agarose beads and immunodetected using anti-NRF2 antibody. For PLA, cells were incubated with anti-Sig1R polyclonal and anti-NRF2 monoclonal antibodies, then subsequently with (−)-mouse and (+)-rabbit PLA probes. For EM analysis, immuno-EM gold labeling was performed using nanogold-enhanced labeling with anti-NRF2 and anti-Sig1R antibodies, and data were confirmed using colloidal gold labeling. The co-IP experiment suggested that NRF2 was bound in a complex with Sig1R. The PLA assays detected abundant orange fluorescence in cones, indicating that Sig1R and NRF2 were within 40 nm of each other. EM immunodetection confirmed co-localization of Sig1R with NRF2 in cells and in mouse retinal tissue. This study is the first to report co-localization of Sig1R-NRF2 and supports earlier studies implicating modulation of NRF2 as a mechanism by which Sig1R mediates retinal neuroprotection.

Rationale: Previous research indicates that the selective sigma-1 receptor ligand PD144418 and the selective sigma-2 ligands YUN-252 can inhibit cocaine-induced hyperactivity. The effects of these ligands on other stimulants, such as methamphetamine, have not been reported. Objectives: The present study examined the effects of PD144418 and YUN-252 pretreatment on methamphetamine-induced hyperactivity after acute treatment. Methods: Mice (n = 8–14/group) were injected with PD144418 (3.16, 10, or 31.6 μmol/kg), YUN-252 (0.316, 3.16, 31.6 μmol/kg), or saline. After 15 min, mice injected with 2.69 μmol/kg methamphetamine or saline vehicle, where distance traveled during a 60-min period was recorded. Additionally, the effect of PD144418 on the initiation and expression of methamphetamine sensitization was determined by treating mice (n = 8–14/group) with PD144418, methamphetamine or saline repeatedly over a 5-day period, and testing said mice with a challenge dose after a 7-day withdrawal period. Results: Results indicate that both PD144418 and YUN-252, in a dose-dependent manner, attenuated hyperactivity induced by an acute methamphetamine injection. Specifically, 10 μmol/kg or 31.6 μmol/kg of PD144418 and 31 μmol/kg of YUN-252 suppressed methamphetamine-induced hyperactivity. In regard to methamphetamine sensitization, while 10 μmol/kg PD144418 prevented the initiation of methamphetamine sensitization, it did not have an effect on the expression. Conclusions: Overall, the current results suggest an intriguing potential for this novel sigma receptor ligand as a treatment for the addictive properties of methamphetamine. Future analysis of this novel sigma receptor ligand in assays directly measuring reinforcement properties will be critical. [ABSTRACT FROM AUTHOR]

Abstract Sigma-1 (σ 1) receptors have been investigated for their involvement in learning, rewarding and motivational processes, particularly as it relates to substances of abuse. Few studies have examined the effects of σ 1 receptor agonists and antagonists on the rewarding and motivational properties of natural reinforcers, such as food. Studies that have investigated σ 1 receptor agonists and antagonists has produced conflicting results. σ 1 receptor antagonist PD144418 has been found to produce a dose-dependent attenuation of locomotor activity induced by cocaine, and by itself, does not suppress basal locomotor activity in mice. However, its effects on reward and motivation as it relates to food are unknown. The present study examined the involvement of σ 1 receptors in mediating the rewarding and motivational properties of food using an operant task. The results indicated that at the highest dose (10 μmol/kg), PD144418 significantly attenuated the number of active lever responses for chow pellets but did not decrease the number of active lever responses for sucrose pellets under a fixed ratio (FR2) schedule of reinforcement. However, under a progressive ratio (PR) reinforcement schedule, 10 μmol/kg of PD14418 significantly reduced the breakpoint, a measure indicative of effort or motivation, for both chow and sucrose pellets. When ad libitum chow or sucrose pellets were made freely available (i.e. no lever press required) inside the operant chamber, 10 μmol/kg, PD144418 did not have an effect on number of pellets consumed. These findings indicate that PD144418 reduces the motivational effort of a food reinforced behavior. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract ABT-737, ABT-263 (Navitoclax) and ABT-199 (Venetoclax) are under intensive preclinical and clinical investigation as treatments for hematologic and other malignancies. These small molecules mimic pro-death B-cell lymphoma-2 (Bcl-2) Homology 3 (BH3) domain-only proteins. They also bear a structural resemblance to certain sigma (σ) receptor ligands. Moreover, the Bcl-2 and σ receptor protein families are both located primarily at the endoplasmic reticulum, mediate cell death and survival through protein–protein interactions, and physically associate. Accordingly, we examined the ability of the ABT series of BH3 mimetics to interact with σ receptors using radioligand-binding techniques. Negative allosteric modulation of [3H](+)-pentazocine, an agonist, binding to σ 1 receptors in guinea pig brain membranes was observed for ABT-737, ABT-263 and ABT-199. Findings included reduction of specific binding to distinct plateaus in concentration-dependent fashion, significant slowing of radioligand dissociation kinetics, and decreases in radioligand affinity with no or modest changes in maximal receptor densities. Using a ternary complex model, dissociation constants (K X) for modulator binding to the σ 1 receptor ranged from 1 to 2.5 μM, while negative cooperativity factors (α), representing the changes in affinity of ligand and modulator when bound as a ternary complex with the receptor, ranged from 0.15 to 0.42. These observations were extended and reinforced by studies using intact small cell (NCI-H69) and non-small cell (NCI-H23) lung cancer cells, and by using an antagonist σ 1 receptor radioligand, E - N -1-(3′-[125I]iodoallyl)- N ′-4-(3″,4″-dimethoxyphenethyl)piperazine, in mouse brain membranes. By contrast, exploratory studies indicate marked enhancement of the σ 2 receptor binding of [3H]1,3-di-(o -tolyl)guanidine/(+)-pentazocine in NCI-H23 cells and guinea pig brain membranes. These findings raise intriguing questions regarding mechanism and potential functional outcomes. [ABSTRACT FROM AUTHOR]

More than four decades passed since sigma receptors were first mentioned. Since then, existence of at least two receptor subtypes and their tissue distributions have been proposed. Nowadays, it is clear, that sigma receptors are unique ubiquitous proteins with pluripotent function, which can interact with so many different classes of proteins. As the endoplasmic resident proteins, they work as molecular chaperones - accompany various proteins during their folding, ensure trafficking of the maturated proteins between cellular organelles and regulate their functions. In the heart, sigma receptor type 1 is more dominant. Cardiac sigma 1 receptors regulate response to endoplasmic reticulum stress, modulates calcium signaling in cardiomyocyte and can affect function of voltage-gated ion channels. They contributed in pathophysiology of cardiac hypertrophy, heart failure and many other cardiovascular disorders. Therefore, sigma receptors are potential novel targets for specific treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Despite the fact that the benzomorphan skeleton has mainly been employed in medicinal chemistry for the development of opioid analgesics, it is a versatile structure. Its stereochemistry, as well as opportune modifications at the phenolic hydroxyl group and at the basic nitrogen, play a pivotal role addressing the benzomorphan-based compounds to a specific target. In this review, we describe the structure activity-relationships (SARs) of benzomorphan-based compounds acting at sigma 1 receptor (σ1R), sigma 2 receptor (σ2R), voltage-dependent sodium channel, N-Methyl- d -Aspartate (NMDA) receptor-channel complex and other targets. Collectively, the SARs data have highlighted that the benzomorphan nucleus could be regarded as a useful template for the synthesis of drug candidates for different targets. [ABSTRACT FROM AUTHOR]

Introduction Sigma-1 receptor is a target for tumor imaging. In a previous study, we synthesized a vesamicol analog, (+)-2-[4-(4-bromophenyl)piperidino]cyclohexanol [(+)- p BrV], with a high affinity for sigma-1 receptor, and synthesized radiobrominated (+)- p BrV. This radiobrominated (+)- p BrV showed high tumor uptake in tumor-bearing mice; however, radioactivity accumulation in normal tissues, such as the liver, was high. We assumed that the accumulation of (+)- p BrV in the non-target tissues was partially derived from its high lipophilicity; therefore, we synthesized and evaluated (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-bromophenol [(+)-BrV-OH], which is a more hydrophilic compound. Although we aimed to develop a PET tracer using 76 Br, in these initial studies, we used 77 Br because of its longer half-life. Methods (+)-[ 77 Br]BrV-OH was synthesized using the chloramine-T method with a radiochemical purity of 95%. Lipophilicity and affinity for sigma-1 receptor of (+)-[ 77 Br]BrV-OH were determined, and biodistribution experiments were performed. We also performed an in vivo blocking study by co-injecting excess amounts of the sigma-1 receptor ligand, SA4503, into mice. Results The lipophilicity and affinity for sigma-1 receptor of (+)-[ 77 Br]BrV-OH were lower than those of (+)-[ 77 Br] p BrV. (+)-[ 77 Br]BrV-OH also showed high tumor uptake in biodistribution experiments in DU-145 tumor-bearing mice,. Although (+)-[ 77 Br] p BrV was retained in most tissues, (+)-[ 77 Br]BrV-OH was cleared from these tissues. In blocking studies, the co-injection of SA4503 significantly decreased the tumor uptake of (+)-[ 77 Br]BrV-OH. Conclusion These results indicate that (+)-[ 76 Br]BrV-OH has potential as a PET probe for sigma-1 receptor imaging. [ABSTRACT FROM AUTHOR]

Background and aims: Progesterone is a female reproductive hormone. Increasing progesterone levels during menstruation or taking synthetic progesterone in oral contraceptives causes some depression in some women. Sigma receptors are considered as new targets in depression medication. Progesterone other than hormonal effects is a neuro-steroid and is an antagonist to sigma receptors. So, the aim of the current study was to investigate the effect of co-concomitant use of progesterone with sigma agonist drugs, dextromethorphan or pentazocine on depression test. Methods: This research is a basic- applied study. Experiments were performed on female mice weighing 25-30 g. The forced swimming test was used to investigate depression. Progesterone 10 mg/kg along with dextromethorphan HBr 30 mg/kg, or pentazocine 2.5 mg/kg were administered on the first day and 30 min before the FST on the second day. Data were analyzed using One-way ANOVA and Tukey tests. Results: Progesterone led to an increase in the immobility time (over 3 minutes) in mice, which is a criterion for animal depression (P<0.05). The immobility of animals was decreased by following consumption of dextromethorphan (100s±13) (P<0.001), and pentazocine (124s±6.9) (P<0.01). These changes were in parallel with antidepression medications by fluvoxamine. Conclusion: Since depression caused by progesterone is resolved by Sigma agonists, Sigma receptors are responsible for depression caused by high doses of progesterone. So, these agonists can be considered as an effective antidepressant in progesterone medications with high dose. [ABSTRACT FROM AUTHOR]

Increasing evidences have implicated that sigma-2 receptor is a biomarker and significantly over-expressed in many proliferative cancer cells with no or low expression in normal cells. Sigma-2 receptor selective ligands have been successfully used as valuable tools to study its pharmacological functions, tumor imaging, and cancer therapeutics or adjuvants. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolinylalkyl benzamides are among a few categories of structures that have demonstrated high affinities and selectivities for sigma-2 receptor and been used extensively as study tools in various tumor imaging and therapy. As a continuous effort, we have synthesized a new series of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives and evaluated their affinities for both sigma-1 and sigma-2 receptors. Most of these newly developed analogs showed good to excellent binding affinities for sigma-2 receptor with no or low affinities for sigma-1 receptor. In particular, compounds 3b , 3e , 4b , and 4e demonstrated K i values of 5–6 nM affinities and excellent selectivities for sigma-2 receptor. In addition, these analogs also demonstrated moderate anticancer activities against human liver Huh-7 tumor cells and human esophagus KYSE-140 cancer cells. But their cytotoxicities seem not to be correlated with their sigma-2 receptor affinities. [ABSTRACT FROM AUTHOR]

Despite considerable advances over the past years in understanding the mechanisms of action and the role of the σ1 receptor, several questions regarding this receptor remain unanswered. This receptor has been identified as a useful target for the treatment of a diverse range of diseases, from various central nervous system disorders to cancer. The recently solved issue of the crystal structure of the σ1 receptor has made elucidating the structure–activity relationship feasible. The interaction of seven representative opioid ligands with the crystal structure of the σ1 receptor (PDB ID: 5HK1) was simulated for the first time using molecular dynamics (MD). Analysis of the MD trajectories has provided the receptor–ligand interaction fingerprints, combining information on the crucial receptor residues and frequency of the residue–ligand contacts. The contact frequencies and the contact maps suggest that for all studied ligands, the hydrophilic (hydrogen bonding) interactions with Glu172 are an important factor for the ligands’ affinities toward the σ1 receptor. However, the hydrophobic interactions with Tyr120, Val162, Leu105, and Ile124 also significantly contribute to the ligand–receptor interplay and, in particular, differentiate the action of the agonistic morphine from the antagonistic haloperidol. [ABSTRACT FROM AUTHOR]

Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent research exploring the molecular function of the sigma-1 receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone activity is activated or inhibited by synthetic sigma-1 receptor ligands in an agonist-antagonist manner. Sigma-1 receptors are localized at the endoplasmic reticulum (ER) membranes that are physically associated with the mitochondria (MAM: mitochondria-associated ER membrane). In specific types of neurons (e.g., those at the spinal cord), sigma-1 receptors are also clustered at ER membranes that juxtapose postsynaptic plasma membranes. Recent studies indicate that sigma-1 receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation. The sigma-1 receptor may thus provide an intracellular drug target that enables controlling ER stress and free radical generation under pathological conditions.

There is currently a significant lack of therapeutic options for acute ischemic stroke, and no drug has been approved for treating patients at delayed time points (≥6 h post-stroke). Afobazole, an anxiolytic currently used clinically in Russia, has been shown to reduce neuronal and glial cell injury in vitro following ischemia. Experiments using the permanent middle cerebral artery occlusion (MCAO) rat model were carried out to determine if afobazole can reduce ischemic stroke damage in vivo and expand the therapeutic window for stroke treatment. Post-stroke (24 h) application of afobazole (0.3–3 mg/kg) significantly decreased infarct volume at 96 h post-surgery, as determined by Fluoro-Jade and NeuN staining of brain sections. Moreover, afobazole helped preserve both the levels and normal histological distribution of myelin basic protein, indicating a reduction in white matter injury. A time-dependence study showed that either pre-treatment or treatment started 6 to 48 h post-stroke with the drug yields improved outcomes at 96 h. The decrease in infarct volume produced by afobazole was blocked by the application of either a σ-1 (BD 1063, 30 mg/kg) or a σ-2 (SM-21, 1 mg/kg) antagonist, indicating that both receptor subtypes are involved in the effects of afobazole. Treatment with afobazole starting at 24 h post-stroke resulted in enhanced survival one month following surgery. Behavioral testing of animals 28–32 days post-surgery using the elevated body swing and forelimb grip-strength tests revealed that treatment with afobazole starting 24 h post-stroke significantly reduces behavioral deficits caused by ischemic stroke. The increase in survival and improved functional outcomes are accompanied by a reduction in infarct volume, as determined by thionin staining of brain sections. Taken together, our data support the use of afobazole as a post-stroke pharmacological agent to expand the current therapeutic window.

Introduction: Considering that donepezil (DPZ) is commonly prescribed for Alzheimer’s disease patients, the aim of the present study was evaluating DPZ antidepressant effect and introducing the possible mechanism. Therefore, nicotinic (mecamylamine) and muscarinic (scopolamine) cholinergic antagonists, as well as neurosteroid sigma antagonist (progesterone) effects, were evaluated concomitantly with DPZ. Materials and Methods: The immobiity time was measured in male mice, in the forced swimming test (FST) as a model of despair, and the number of marbles buried (MBT) in an open field was assessed as the model of obsessive-compulsive behavior in mice, the tests were verified by fluoxetine. Results and Conclusion: DPZ (1 mg/kg) reduced the immobility time in the FST (117 ± 4.8 s vs. control group 173 ± 3.7 s), the change was similar to fluoxetine (20 mg/kg), which reduced immobility to 52 ± 15 s. The number of marbles buried was reduced by DPZ to 50% in the MBT. Scopolamine (0.5 mg/kg) and mecamylamine (1 mg/kg) that were used concomitantly with DPZ augmented the antidepressant effects of DPZ. While high-dose progesterone (10 mg/kg) not only increased the immobility time (169 ± 7.1 s) but also reversed DPZ effects on the MBT. Conclusion: DPZ agonistic effects on sigma-1 receptor could be responsible for its effects on the immobility time in FST which indicates its antidepression effects. Thus, DPZ should be considered in clinical research for treating depression or obsession in patients with a history of cognition problems, or as an antidepressant in senile dementia. [ABSTRACT FROM AUTHOR]

A 3D quantitative structure-activity relationship (3D-QSAR) model for predicting the σ 2 receptor affinity has been constructed with the aim of providing a useful tool for the identification, design, and optimization of novel σ 2 receptor ligands. The model has been built using a set of 500 selective σ 2 receptor ligands recovered from the sigma-2 receptor selective ligand database (S2RSLDB) and developed with the software Forge. The present model showed high statistical quality as confirmed by its robust predictive potential and satisfactory descriptive capability. The drawn up 3D map allows for a prompt visual comprehension of the electrostatic, hydrophobic, and shaping features underlying σ 2 receptor ligands interaction. A theoretic approach for the generation of new lead compounds with optimized σ 2 receptor affinity has been performed by means of scaffold hopping analysis. Obtained results further confirmed the validity of our model being some of the identified moieties have already been successfully employed in the development of potent σ 2 receptor ligands. For the first time is herein reported a 3D-QSAR model which includes a number of chemically diverse σ 2 receptor ligands and well accounts for the individual ligands affinities. These features will ensure prospectively advantageous applications to speed up the identification of new potent and selective σ 2 receptor ligands. [ABSTRACT FROM AUTHOR]

For the first time in sigma-2 (σ 2 ) receptor field, a quantitative structure–activity relationship (QSAR) model has been built using p K i values of the whole set of known selective σ 2 receptor ligands (548 compounds), taken from the Sigma-2 Receptor Selective Ligands Database (S2RSLDB) ( http://www.researchdsf.unict.it/S2RSLDB/ ), through the Monte Carlo technique and employing the software CORAL. The model has been developed by using a large and structurally diverse set of compounds, allowing for a prediction of different populations of chemical compounds endpoint (σ 2 receptor p K i ). The statistical quality reached, suggested that model for p K i determination is robust and possesses a satisfactory predictive potential. The statistical quality is high for both visible and invisible sets. The screening of the FDA approved drugs, external to our dataset, suggested that sixteen compounds might be repositioned as σ 2 receptor ligands (predicted p K i ≥ 8). A literature check showed that six of these compounds have already been tested for affinity at σ 2 receptor and, of these, two (Flunarizine and Terbinafine) have shown an experimental σ 2 receptor p K i > 7. This suggests that this QSAR model may be used as focusing screening filter in order to prospectively find or repurpose new drugs with high affinity for the σ 2 receptor, and overall allowing for an enhanced hit rate respect to a random screening. [ABSTRACT FROM AUTHOR]

Glial cells play a critical role in neuronal support which includes the production and release of the neurotrophin brain-derived neurotrophic factor (BDNF). Activation of the sigma-1 receptor (S1R) has been shown to attenuate inflammatory stress-mediated brain injuries, and there is emerging evidence that this may involve a BDNF-dependent mechanism. In this report we studied S1R-mediated BDNF release from human astrocytic glial cells. Astrocytes express the S1R, which mediates BDNF release when stimulated with the prototypical S1R agonists 4-PPBP and (+)-SKF10047. This effect could be antagonized by a selective concentration of the S1R antagonist BD1063. Haloperidol is known to have high affinity interactions with the S1R, yet it was unable to facilitate BDNF release. Remarkably, however, two metabolites of haloperidol, haloperidol I and haloperidol II (reduced haloperidol), were discovered to facilitate BDNF secretion and this effect was antagonized by BD1063. Neither 4-PPBP, nor either of the haloperidol metabolites affected the level of BDNF mRNA as assessed by qPCR. These results demonstrate for the first time that haloperidol metabolites I and II facilitate the secretion of BDNF from astrocytes by acting as functionally selective S1R agonists. [ABSTRACT FROM AUTHOR]

As sigma receptors are abundantly expressed on different types of cancer cells, several radiolabeled sigma receptor ligands have been developed for cancer imaging and therapy. Previously, we synthesized and evaluated radioiodinated aza-vesamicol derivatives, [125I] p IC 3 NV, [125I] m IC 2 N5V, and [125I] m IC 3 N5V. They accumulated in tumors, and [125I] m IC 2 N5V and [125I] m IC 3 N5V showed higher tumor to non-target tissue ratios than [125I] p IC 3 NV. Therefore, we synthesized and evaluated the corresponding 211At-labeled compounds, [211At] m AtC 2 N5V and [211At] m AtC 3 N5V, for targeted alpha therapy (TAT). [211At] m AtC 2 N5V and [211At] m AtC 3 N5V were prepared by the standard method of electrophilic astatodestannylation of the corresponding trimethylstannyl precursors. Cellular uptake experiments, and biodistribution experiments and therapeutic experiments in tumor-bearing mice were performed. The radiochemical yields of [211At] m AtC 2 N5V and [211At] m AtC 3 N5V were 45.5 ± 14.4% and 56.9 ± 13.8%, respectively. After HPLC purification, their radiochemical purities were over 95%. [211At] m AtC 2 N5V and [211At] m AtC 3 N5V showed high uptake in DU-145 cells. They demonstrated high accumulation in tumors (6.9 ± 1.4%injected dose/g and 5.1 ± 1.4%injected dose/g at 1 h, respectively) and similar biodistribution tendencies compared with the corresponding 125I-labeled compounds. A single injection of [211At] m AtC 2 N5V (0.48 MBq) or [211At] m AtC 3 N5V (0.48 MBq) significantly inhibited tumor growth. These results indicated that [211At] m AtC 2 N5V and [211At] m AtC 3 N5V could be potential candidates for TAT. [Display omitted] [ABSTRACT FROM AUTHOR]