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Journal of Medicinal Chemistry Sep 2022To better understand the role of dopamine D receptor (DR) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for DR were...
To better understand the role of dopamine D receptor (DR) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for DR were discovered starting from the brain penetrant and DR selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1)-one (). In particular, the DR antagonist , showing the highest affinity and selectivity over DR and DR within the series (D/D = 8318, D/D = 3715), and the biased ligand , partially activating DR G-/G-protein and blocking β-arrestin recruitment, emerged as the most interesting compounds. These compounds, evaluated for their GBM antitumor activity, induced a decreased viability of GBM cell lines and primary GBM stem cells (GSC#83), with the maximal efficacy being reached at a concentration of 10 μM. Interestingly, the treatment with both compounds and induced an increased effect in reducing the cell viability with respect to temozolomide, which is the first-choice chemotherapeutic drug in GBM.
Topics: Dopamine Antagonists; Glioblastoma; Humans; Ligands; Receptors, Dopamine D4; Temozolomide; beta-Arrestins
PubMed: 36098685
DOI: 10.1021/acs.jmedchem.2c00840 -
The Annals of Pharmacotherapy Feb 2015To evaluate the safety and efficacy of droperidol for the relief of acute migraine headaches. (Review)
Review
OBJECTIVE
To evaluate the safety and efficacy of droperidol for the relief of acute migraine headaches.
DATA SOURCES
A MEDLINE search (1946 to August 2014) was performed using the following keywords and associated medical subject headings: droperidol, inapsine, headache, migraine, and migraine disorder.
STUDY SELECTION AND DATA EXTRACTION
The search was conducted to identify randomized controlled trials comparing droperidol with placebo or an active control in adult patients with acute migraine headaches that were published in English. Primary end points included acute headache improvement after the intervention. Safety end points included the frequency of extrapyramidal symptoms, somnolence, and cardiac adverse effects.
DATA SYNTHESIS
In all, 5 manuscripts are included in this review. Patients presenting to the emergency department with acute headache desire rapid pain relief, which was the primary objective in each of the evaluated studies. Droperidol was better than placebo and at least as effective as comparator drugs such as prochlorperazine, meperidine, or olanzapine using droperidol doses of 2.5 to 5 mg, given either intramuscularly (IM) or intravenously (IV). The most commonly reported adverse effects were extrapyramidal symptoms and sedation. Cardiac adverse effects were not reported in any of the studies; however, only 2 articles described using cardiac monitoring.
CONCLUSIONS
Parenteral droperidol is an effective option for the treatment of acute migraine. The minimum effective dose is 2.5 mg given IM or IV. Clinicians must be aware of the risk for adverse events, select appropriate patients, perform EKG monitoring for patients at risk of QTc prolongation, and institute treatment if necessary.
Topics: Acute Disease; Dopamine Antagonists; Droperidol; Humans; Migraine Disorders; Randomized Controlled Trials as Topic
PubMed: 25416184
DOI: 10.1177/1060028014554445 -
Pharmacogenomics Jul 2016
Topics: Dopamine Antagonists; Genetic Variation; Humans; Mental Disorders; Pharmacogenomic Variants; Receptors, Dopamine D2; Treatment Outcome
PubMed: 27377823
DOI: 10.2217/pgs-2016-0087 -
Neurological Research Oct 2022We aimed to investigate the hypothesis that sigma receptor ligands, haloperidol and ifenprodil, attenuate hypoxia-induced striatal dopamine release in vitro and...
OBJECTIVE
We aimed to investigate the hypothesis that sigma receptor ligands, haloperidol and ifenprodil, attenuate hypoxia-induced striatal dopamine release in vitro and determine the possible mechanisms.
METHODS
Extracellular concentrations of dopamine were measured using acute brain slices method under hypoxic, aglycemic and ischemic conditions. Sigma receptor ligands haloperidol and ifenprodil attenuate striatal dopamine release induced by hypoxia in contrast to aglycemia and ischemia. To determine the possible contribution of glutamatergic system on this effect, we compared the effect of NMDA receptor antagonist MK-801 and haloperidol in hypoxia induced by Na-K-ATPaz enzyme inhibitor ouabain. Also, we compared the effect of dopamine uptake blocker nomifensine and haloperidol to determine the role of dopamine transporter on this effect.
RESULTS
Haloperidol and nomifensine almost completely abolish ouabain-induced dopamine release unlike MK-801. Different effects of sigma ligands and glutamate receptor antagonists on the hypoxia and ouabain induced dopamine release show that glutamate receptor blockade is partial involved in inhibitory effect of sigma ligand on dopamine release under hypoxic conditions. Similar effect of dopamine uptake blocker nomifensine and sigma receptor ligand haloperidol on ouabain induced dopamine release supports the possibility that inhibition of reverse dopamine transport by sigma ligands might be involved in their protective effect.
CONCLUSIONS
Data in this study suggest that sigma ligands may be a new therapeutic intervention for the management of hypoxic conditions.
Topics: Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Haloperidol; Hypoxia; Ligands; Nomifensine; Ouabain; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, sigma
PubMed: 35499231
DOI: 10.1080/01616412.2022.2072100 -
ENeuro 2022The orbitofrontal cortex (OFC) and piriform cortex (Pir) play a role in fentanyl relapse after food choice-induced voluntary abstinence, a procedure mimicking abstinence...
The orbitofrontal cortex (OFC) and piriform cortex (Pir) play a role in fentanyl relapse after food choice-induced voluntary abstinence, a procedure mimicking abstinence because of availability of alternative nondrug rewards. We used hybridization and pharmacology to determine the role of OFC and Pir cannabinoid and dopamine receptors in fentanyl relapse. We trained male and female rats to self-administer food pellets for 6 d (6 h/d) and intravenous fentanyl (2.5 µg/kg/infusion) for 12 d (6 h/d). We assessed fentanyl relapse after 12 discrete choice sessions between fentanyl and food (20 trials/d), in which rats voluntarily reduced fentanyl self-administration. We used RNAscope to determine whether fentanyl relapse is associated with activity (indicated by ) in OFC and Pir cells expressing [which encodes cannabinoid 1 (CB1) receptors] or and (which encode dopamine D1 and D2 receptors). We injected a CB1 receptor antagonist or agonist (0.3 or 1.0 µg AM251 or WIN55,212-2/hemisphere) into OFC or a dopamine D1 receptor antagonist (1.0 or 3.0 µg SCH39166/hemisphere) into Pir to determine the effect on fentanyl relapse. Fentanyl relapse was associated with OFC cells co-expressing and and Pir cells co-expressing and However, injections of the CB1 receptor antagonist AM251 or agonist WIN55,212-2 into OFC or the dopamine D1 receptor antagonist SCH39166 into Pir had no effect on fentanyl relapse. Fentanyl relapse is associated with activation of -expressing OFC cells and -expressing Pir cells, but pharmacological manipulations do not support causal roles of OFC CB1 receptors or Pir dopamine D1 receptors in fentanyl relapse.
Topics: Animals; Cannabinoids; Dopamine; Dopamine Antagonists; Female; Fentanyl; Male; Piriform Cortex; Rats; Receptor, Cannabinoid, CB1; Receptors, Dopamine D1; Recurrence
PubMed: 35768212
DOI: 10.1523/ENEURO.0496-21.2022 -
Translational Psychiatry Jul 2016Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the... (Randomized Controlled Trial)
Randomized Controlled Trial
Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity.
Topics: Amisulpride; Cues; Delay Discounting; Dopamine Antagonists; Double-Blind Method; Female; Healthy Volunteers; Humans; Impulsive Behavior; Male; Naltrexone; Narcotic Antagonists; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Opioid, mu; Reward; Sulpiride; Young Adult
PubMed: 27378550
DOI: 10.1038/tp.2016.113 -
Brain Research Bulletin Apr 2023Stress contributes to pain sensation by affecting several neural pathways, including mesolimbic-cortical dopamine neurons. Nucleus accumbens, an essential element of the...
Stress contributes to pain sensation by affecting several neural pathways, including mesolimbic-cortical dopamine neurons. Nucleus accumbens, an essential element of the mesolimbic dopaminergic pathway, plays a fundamental role in modulating pain and is differentially influenced by stressful events. Since we previously demonstrated the marked association of intra-NAc dopamine receptors with forced swim stress-evoked analgesia in acute pain state, this research was conducted to consider the contribution of intra-accumbal D1- and D2-like dopamine receptors to modulating effects of exposure to restraint stress in pain-related behaviors during the tail-flick test. Stereotaxic surgery was executed to implant a guide cannula within the NAc in male Wistar rats. On the test day, different concentrations of SCH23390 and Sulpiride as D1- and D2-like dopamine receptor antagonists, respectively, were unilaterally microinjected within the NAc. The vehicle animals received saline or 12 % DMSO (0.5 µl) instead of SCH23390 or Sulpiride into the NAc, respectively. Five minutes following receiving drug or vehicle, animals were restrained for 3 h and then their acute nociceptive threshold was measured for a 60-min period by the tail-flick test. Our data revealed that RS considerably enhanced antinociceptive reaction in acute pain states. The analgesia evoked by RS dramatically declined following blocking either D1- or D2-like dopamine receptors in the NAc, an effect was more noticeable by D1-like dopamine receptor antagonist. These findings indicated that intra-NAc dopamine receptors are considerably mediated in the RS-produced analgesia in acute pain states, suggesting their possible role in psychological stress and disease.
Topics: Rats; Animals; Male; Sulpiride; Rats, Wistar; Acute Pain; Receptors, Dopamine D2; Receptors, Dopamine D1; Dopamine Antagonists; Nucleus Accumbens; Analgesics
PubMed: 36889361
DOI: 10.1016/j.brainresbull.2023.03.003 -
Journal of Experimental & Clinical... Jan 2024Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study...
BACKGROUND
Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context.
METHODS
GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo.
RESULTS
Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice.
CONCLUSIONS
DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.
Topics: Animals; Humans; Mice; Brain; CCAAT-Enhancer-Binding Proteins; Dopamine; Glioblastoma; Glioma; Mice, Nude; Multigene Family; Receptors, Dopamine D1; Ubiquitin-Protein Ligases; Dopamine Antagonists; Proto-Oncogene Proteins c-myc
PubMed: 38246990
DOI: 10.1186/s13046-024-02947-7 -
ELife Oct 2020The observation of animal orofacial and behavioral reactions has played a fundamental role in research on reward but is seldom assessed in humans. Healthy volunteers (N...
The observation of animal orofacial and behavioral reactions has played a fundamental role in research on reward but is seldom assessed in humans. Healthy volunteers (N = 131) received 400 mg of the dopaminergic antagonist amisulpride, 50 mg of the opioidergic antagonist naltrexone, or placebo. Subjective ratings, physical effort, and facial reactions to matched primary social (affective touch) and nonsocial (food) rewards were assessed. Both drugs resulted in lower physical effort and greater negative facial reactions during reward anticipation, especially of food rewards. Only opioidergic manipulation through naltrexone led to a reduction in positive facial reactions to liked rewards during reward consumption. Subjective ratings of wanting and liking were not modulated by either drug. Results suggest that facial reactions during anticipated and experienced pleasure rely on partly different neurochemical systems, and also that the neurochemical bases for food and touch rewards are not identical.
Topics: Adult; Amisulpride; Dopamine Antagonists; Emotions; Female; Food; Humans; Male; Naltrexone; Narcotic Antagonists; Pleasure; Reward; Young Adult
PubMed: 33046213
DOI: 10.7554/eLife.55797 -
Biomedicine & Pharmacotherapy =... Jun 2021Several brain neurotransmitters, including histamine (HA), acetylcholine (ACh), and dopamine (DA) are suggested to be involved in several brain disorders including...
Several brain neurotransmitters, including histamine (HA), acetylcholine (ACh), and dopamine (DA) are suggested to be involved in several brain disorders including cognitive deficits, depression, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with Autism spectrum disorder (ASD). Therefore, the ameliorative effects of the novel multiple-active compound ST-713 with high binding affinities at histamine H3 receptor (H3R), dopamine D2sR and D3R on ASD-like behaviors in male BTBR T+tf/J mice model were assessed. ST-713 (3-(2-chloro-10H-phenothiazin-10-yl)-N-methyl-N-(4-(3-(piperidin-1-yl)propoxy)benzyl)propan-1-amine; 2.5, 5, and 10 mg/kg, i.p.) ameliorated dose-dependently social deficits, and significantly alleviated the repetitive/compulsive behaviors of BTBR mice (all P < 0.05). Moreover, ST-713 modulated disturbed anxiety levels, but failed to obliterate increased hyperactivity of tested mice. Furthermore, ST-713 (5 mg/kg) attenuated the increased levels of hippocampal and cerebellar protein expressions of NF-κB p65, COX-2, and iNOS in BTBR mice (all P < 0.05). The ameliorative effects of ST-713 on social parameters were entirely reversed by co-administration of the H3R agonist (R)-α-methylhistamine or the anticholinergic drug scopolamine. The obtained results demonstrate the potential of multiple-active compounds for the therapeutic management of neuropsychiatric disorders, e.g. ASD.
Topics: Animals; Autistic Disorder; Cerebellum; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Hippocampus; Histamine Antagonists; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Histamine H3
PubMed: 33773463
DOI: 10.1016/j.biopha.2021.111517