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British Journal of Pharmacology Nov 2018Target binding kinetics influence the time course of the drug effect (pharmacodynamics) both (i) directly, by affecting the time course of target occupancy, driven by...
BACKGROUND AND PURPOSE
Target binding kinetics influence the time course of the drug effect (pharmacodynamics) both (i) directly, by affecting the time course of target occupancy, driven by the pharmacokinetics of the drug, competition with endogenous ligands and target turnover, and (ii) indirectly, by affecting signal transduction and homeostatic feedback. For dopamine D receptor antagonists, it has been hypothesized that fast receptor binding kinetics cause fewer side effects, because part of the dynamics of the dopaminergic system is preserved by displacement of these antagonists.
EXPERIMENTAL APPROACH
Target binding kinetics of D receptor antagonists and signal transduction after dopamine and D receptor antagonist exposure were measured in vitro. These data were integrated by mechanistic modelling, taking into account competitive binding of endogenous dopamine and the antagonist, the turnover of the second messenger cAMP and negative feedback by PDE turnover.
KEY RESULTS
The proposed signal transduction model successfully described the cellular cAMP response for 17 D receptor antagonists with widely different binding kinetics. Simulation of the response to fluctuating dopamine concentrations revealed that a significant effect of the target binding kinetics on the dynamics of the signalling only occurs at endogenous dopamine concentration fluctuations with frequencies below 1 min .
CONCLUSIONS AND IMPLICATIONS
Signal transduction and feedback are important determinants of the time course of drug effects. The effect of the D receptor antagonist dissociation rate constant (k ) is limited to the maximal rate of fluctuations in dopamine signalling as determined by the dopamine k and the cAMP turnover.
Topics: Animals; Binding Sites; CHO Cells; Cricetulus; Dopamine; Dopamine Antagonists; Kinetics; Models, Biological; Receptors, Dopamine D2; Signal Transduction
PubMed: 30051456
DOI: 10.1111/bph.14456 -
Pharmacology, Biochemistry, and Behavior May 2016Despite the high prevalence of methamphetamine (METH) use, no FDA-approved pharmacological treatment is currently available for individuals with a METH addiction....
Despite the high prevalence of methamphetamine (METH) use, no FDA-approved pharmacological treatment is currently available for individuals with a METH addiction. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance derived from corydalis and stephania that has been used in traditional Asian medicine for its analgesic, sedative and hypnotic properties. Previous pharmacological studies of l-THP indicated that it not only binds to D1 and D2 receptors but also has a low affinity for D3 receptors and may function as an antagonist. The unique pharmacological profile of l-THP suggests that it may have potential therapeutic effects on drug addiction; however, the effects of l-THP in individuals with METH addictions are largely unknown. In this study, we investigated the effects of l-THP on METH self-administration and METH-induced reinstatement. In our experiments, l-THP (1.25, 2.50 and 5.00 mg/kg, i.p.) decreased METH self-administration under the fixed-ratio 1 schedule. l-THP (2.50 and 5.00 mg/kg, i.p) also prevented the METH-induced reinstatement of METH-seeking behaviors. Interestingly, l-THP (1.25 and 2.50mg/kg, i.p) did not affect locomotor activity following METH injection (1mg/kg) suggesting that the observed effects of l-THP (2.50mg/kg) on METH-induced reinstatement were not due to motor impairments. Thus, l-THP (a natural, mixed dopamine (DA) receptor antagonist) attenuates METH self-administration and METH-induced reinstatement.
Topics: Animals; Berberine Alkaloids; Dopamine Antagonists; Locomotion; Male; Methamphetamine; Rats; Rats, Sprague-Dawley; Self Administration
PubMed: 26806555
DOI: 10.1016/j.pbb.2016.01.010 -
European Journal of Pharmacology Jan 2021F17464 (N-(3-{4-[4-(8-Oxo-8H-[1,3]-dioxolo-[4,5-g]-chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide, hydrochloride) is a new potential antipsychotic with...
F17464 (N-(3-{4-[4-(8-Oxo-8H-[1,3]-dioxolo-[4,5-g]-chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide, hydrochloride) is a new potential antipsychotic with a unique profile. The compound exhibits high affinity for the human dopamine receptor subtype 3 (hD) (K = 0.17 nM) and the serotonin receptor subtype 1a (5-HT) (K = 0.16 nM) and a >50 fold lower affinity for the human dopamine receptor subtype 2 short and long form (hD) (K = 8.9 and 12.1 nM, respectively). [C]F17464 dynamic studies show a slower dissociation rate from hD receptor (t1/2 = 110 min) than from hD receptor (t1/2 = 1.4 min) and functional studies demonstrate that F17464 is a D receptor antagonist, 5-HT receptor partial agonist. In human dopaminergic neurons F17464 blocks ketamine induced morphological changes, an effect D receptor mediated. In vivo F17464 target engagement of both D and 5-HT receptors is demonstrated in displacement studies in the mouse brain. F17464 increases dopamine release in the rat prefrontal cortex and mouse lateral forebrain - dorsal striatum and seems to reduce the effect of MK801 on % c-fos mRNA medium expressing neurons in cortical and subcortical regions. F17464 also rescues valproate induced impairment in a rat social interaction model of autism. All the neurochemistry and behavioural effects of F17464 are observed in the dose range 0.32-2.5 mg/kg i.p. in both rats and mice. The in vitro - in vivo pharmacology profile of F17464 in preclinical models is discussed in support of a therapeutic use of the compound in schizophrenia and autism.
Topics: Animals; Antipsychotic Agents; Autistic Disorder; Behavior, Animal; Benzopyrans; Biogenic Monoamines; Brain; Catalepsy; Cells, Cultured; Dopamine; Dopamine Antagonists; Dopaminergic Neurons; Female; Genes, fos; Male; Mice; Neuronal Plasticity; Piperazines; Prolactin; Rats, Sprague-Dawley; Receptors, Dopamine D3; Sulfonamides; Valproic Acid; Rats
PubMed: 33065094
DOI: 10.1016/j.ejphar.2020.173635 -
Bioorganic & Medicinal Chemistry Letters Apr 2022The dopamine receptor 4 (DR) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the...
The dopamine receptor 4 (DR) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the brain, there is mounting evidence pointing to a role for the DR in the modulation of this network and its subsequent involvement in l-DOPA induced dyskinesias in Parkinson's disease. As part of our continued effort in the discovery of novel DR antagonists, we report the discovery and characterization of a new 3- or 4-benzyloxypiperidine scaffold as DR antagonists. We report several DR selective compounds (>30-fold vs. other dopamine receptor subtypes) with improved in vitro and in vivo stability over previously reported DR antagonists.
Topics: Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Piperidines; Receptors, Dopamine D4; Structure-Activity Relationship
PubMed: 35151866
DOI: 10.1016/j.bmcl.2022.128615 -
Journal of Psychopharmacology (Oxford,... Nov 2018
Topics: Animals; Dopamine Antagonists; Drug Development; Drug Evaluation, Preclinical; Humans; Receptors, Dopamine D1
PubMed: 30354927
DOI: 10.1177/0269881118799380 -
ACS Chemical Neuroscience May 2024The compound -(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast...
The compound -(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α-adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α-adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a β-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.
Topics: Animals; Antidepressive Agents; Benzamides; Mice; Male; Dopamine Antagonists; Dopamine; Hindlimb Suspension; Organoselenium Compounds
PubMed: 38639539
DOI: 10.1021/acschemneuro.4c00092 -
Psychopharmacology Sep 2017Signals carried by the mesencephalic dopamine system and conveyed to anterior cingulate cortex are critically implicated in probabilistic reward learning and performance... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Signals carried by the mesencephalic dopamine system and conveyed to anterior cingulate cortex are critically implicated in probabilistic reward learning and performance monitoring. A common evaluative mechanism purportedly subserves both functions, giving rise to homologous medial frontal negativities in feedback- and response-locked event-related brain potentials (the feedback-related negativity (FRN) and the error-related negativity (ERN), respectively), reflecting dopamine-dependent prediction error signals to unexpectedly negative events. Consistent with this model, the dopamine receptor antagonist, haloperidol, attenuates the ERN, but effects on FRN have not yet been evaluated.
METHODS
ERN and FRN were recorded during a temporal interval learning task (TILT) following randomized, double-blind administration of haloperidol (3 mg; n = 18), diphenhydramine (an active control for haloperidol; 25 mg; n = 20), or placebo (n = 21) to healthy controls. Centroparietal positivities, the Pe and feedback-locked P300, were also measured and correlations between ERP measures and behavioral indices of learning, overall accuracy, and post-error compensatory behavior were evaluated. We hypothesized that haloperidol would reduce ERN and FRN, but that ERN would uniquely track automatic, error-related performance adjustments, while FRN would be associated with learning and overall accuracy.
RESULTS
As predicted, ERN was reduced by haloperidol and in those exhibiting less adaptive post-error performance; however, these effects were limited to ERNs following fast timing errors. In contrast, the FRN was not affected by drug condition, although increased FRN amplitude was associated with improved accuracy. Significant drug effects on centroparietal positivities were also absent.
CONCLUSIONS
Our results support a functional and neurobiological dissociation between the ERN and FRN.
Topics: Adult; Brain; Brain Mapping; Dopamine Antagonists; Double-Blind Method; Electroencephalography; Evoked Potentials; Female; Haloperidol; Humans; Learning; Male; Middle Aged; Reward; Young Adult
PubMed: 28601965
DOI: 10.1007/s00213-017-4645-2 -
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 -
CNS Spectrums Dec 2016The broad use of atypical antipsychotics was expected to dramatically reduce the prevalence and incidence of tardive dyskinesia (TD), but data show that TD remains an... (Review)
Review
The broad use of atypical antipsychotics was expected to dramatically reduce the prevalence and incidence of tardive dyskinesia (TD), but data show that TD remains an important challenge due the persistent nature of its symptoms and resistance to numerous treatment modalities, including antipsychotic discontinuation. Recent insights on genetic risk factors and new concepts surrounding pathophysiology have spurred interest in the possibility of targeted treatment for TD. As will be reviewed in this article, the number of evidence-based strategies for TD treatment is small: only clonazepam, amantadine, ginkgo biloba extract, and the vesicular monoamine transporter 2 (VMAT2) inhibitor tetrabenazine have compelling data. Using new insights into the metabolism of tetrabenazine and the properties of its active metabolites, 2 modifications of tetrabenazine have been synthesized to improve the kinetic profile, and are currently involved in double-blind placebo controlled studies aimed at U.S. Food and Drug Administration (FDA) regulatory approval. The possible availability of these new agents, deuterated tetrabenazine and valbenazine, significantly widens the range of treatment choices for patients with TD. For clinicians with patients at risk for TD due to dopamine antagonist exposure, experience has shown that the problem of TD will be an ongoing issue in modern psychiatry, and that an appreciation of new developments in the pathophysiology of, risk factors for, and treatment of TD is crucial to managing this condition.
Topics: Adrenergic Uptake Inhibitors; Amantadine; Antipsychotic Agents; Clonazepam; Dopamine Agents; Dopamine Antagonists; GABA Modulators; Ginkgo biloba; Humans; Plant Extracts; Risk Factors; Tardive Dyskinesia; Tetrabenazine; Valine
PubMed: 28044943
DOI: 10.1017/S1092852916000730 -
Brain Research Bulletin Apr 2022Beta band (12-30 Hz) hypersynchrony within the basal ganglia-thalamocortical network has been suggested as a hallmark of Parkinson's disease (PD) pathophysiology....
Beta band (12-30 Hz) hypersynchrony within the basal ganglia-thalamocortical network has been suggested as a hallmark of Parkinson's disease (PD) pathophysiology. Abnormal beta band oscillations are found in the pedunculopontine nucleus (PPN) and primary motor cortex (M1) and are correlated with dopamine depletion. Dopamine acts locomotion and motor performance mainly through dopamine receptors (D1 and D2). However, the precise mechanism by which dopamine receptors regulate beta band electrophysiological activities between the PPN and M1 is still unknown. Here, we recorded the neuronal activity of the PPN and M1 simultaneously by the administration of the drug (SCH23390 and raclopride), selectively blocking the dopamine D1 receptor and D2 receptor. We discovered that the increased coherent activity of the beta band (12-30 Hz) between M1 and PPN in the lesioned group could be reduced and restored by injecting raclopride in the resting and wheel running states. Our studies revealed the unique role of D2 dopamine receptor signaling in regulating β band oscillatory activity in M1 and PPN and their relationship after the loss of dopamine, which contributes to elucidating the underlying mechanism of the pathophysiology of PD.
Topics: Animals; Benzazepines; Beta Rhythm; Disease Models, Animal; Dopamine Antagonists; Motor Cortex; Parkinson Disease; Pedunculopontine Tegmental Nucleus; Raclopride; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 35077843
DOI: 10.1016/j.brainresbull.2022.01.012