Endogenous opiates and behavior: 2022

Peptides, Journal Year: 2023, Volume and Issue: 169, P. 171095 - 171095

Published: Sept. 12, 2023

Language: Английский

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Effects of selective dopamine D3 receptor partial agonist/antagonists on oxycodone self-administration and antinociception in monkeys

Neuropsychopharmacology, Journal Year: 2023, Volume and Issue: 48(12), P. 1716 - 1723

Published: April 28, 2023

Language: Английский

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Decoding the Structure–Activity Relationship of the Dopamine D3 Receptor-Selective Ligands Using Machine and Deep Learning Approaches

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: May 29, 2025

Dysfunctions of the dopamine D2 and D3 receptors (D2 D3) are implicated in neuropsychiatric conditions such as Parkinson's disease, schizophrenia, substance use disorders (SUDs). Evidence indicates that D3-selective ligands can effectively modulate reward pathways, offering potential treating SUDs with reduced side effects. However, high homology between presents challenges developing subtype-selective ligands, crucial for elucidating receptor-specific functions targeted therapeutics. Here, to facilitate selective ligand discovery, we leveraged ligand-based quantitative structure-activity relationship (QSAR) modeling approaches predict binding affinity at D3, well selectivity D3. We first queried training data from ChEMBL database performed a systematic curation process enhance quality. then developed QSAR models using eXtreme Gradient Boosting, random forest, deep neural network (DNN) algorithms, DNN benefiting novel hyperparameter optimization protocol. All exhibited strong predictive performance, DNN-based slightly but consistently outperforming tree-based models. Integrating predictions all algorithms into consensus metric further improved accuracy robustness. Notably, our outperformed models, likely due noise cancellation achieved by subtracting affinities two receptors. The Shapley Additive explanations analysis revealed key pharmacophoric physicochemical features critical receptor selectivity, while molecular docking representative compounds highlighted structural basis selectivity. These findings provide robust framework QSARs advancing rational design therapeutics these

Language: Английский

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Linkers in Bitopic Agonists Shape Bias Profile among Transducers for the Dopamine D2 and D3 Receptors

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 7(8), P. 2333 - 2349

Published: July 26, 2024

Bitopic ligands bind both orthosteric and allosteric or secondary binding sites within the same receptor, often resulting in an improvement of receptor selectivity, potency, efficacy. In particular, for agonists antagonists dopamine D2 D3 receptors (D2R D3R), primary therapeutic targets several neurological neuropsychiatric disorders, bitopic ligand design has proved advantageous achieving better pharmacological profiles vitro. Although two pharmacophores a are typically considered main drivers conformational change role linker that connects not yet been systematically studied its relevance activity profiles. Here, we present comprehensive analysis sumanirole PF592,379-based indole-containing compounds agonist at D2R D3R, with focus on chemical space stereochemistry through testing six distinct chirally resolved linkers simple aliphatic linker. The structure relationships (SARs) these examined extensively, beyond conventional level, by characterizing activation all putative transducers over 44 min time course. Our multiparametric reveals previously unappreciated specific linker-dependent effects pharmacophores, receptors, transducer kinetics, bias, highlighting utility this approach significance type shaping bias

Language: Английский

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Brexpiprazole in patients with schizophrenia with or without substance use disorder: an observational study

Frontiers in Psychiatry, Journal Year: 2023, Volume and Issue: 14

Published: Dec. 4, 2023

Partial dopamine D2 receptor agonists are used for psychotic symptoms in adults with schizophrenia spectrum disorders. Recently, interest surged partial substance use disorders (SUDs). Since it is believed that SUDs decrease the efficacy of pharmacotherapy underlying psychiatric disorders, we tested agonist brexpiprazole patients who were either comorbid a SUD (SUD group) or not (non-SUD) to assess treatment response and effect on craving SUD.We included DSM-5/DSM-5-TR (using SCID-5-CV) aged 18-66 years non-SUD treat 4 mg/day 6 months during February-October 2022. Patients assessed Clinical Global Impressions-Severity (CGI-S) scale, 24-item Brief Psychiatric Rating Scale (BPRS), Positive And Negative Syndrome (PANSS) at baseline, weekly first 2 monthly next four. Furthermore, visual analog scale (VAScrav) same timepoints.The total sample was 86 (85 analysable) 18- 64-year-old (mean 39.32 ± 14.09) [51 men (59.3%) 35 women (40.7%)], whom 48 (55.8%) (37 11 women) 38 (44.2%) (14 24 women). No serious persistent adverse events developed over study period, but one patient dropped out subjective akathisia. Results indicated main effects time improvements course CGI-S, BPRS, PANSS both groups entire sample, VAScrav SUD. Brexpiprazole associated similar significant month endpoint compared baseline.Treatment improved schizophrenia, independently from whether they belonged group; hence, comorbidity did confer resistance brexpiprazole. group, observed reduced craving.

Language: Английский

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Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis

Molecules, Journal Year: 2022, Volume and Issue: 28(1), P. 178 - 178

Published: Dec. 25, 2022

Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays a hot topic in medicinal chemistry. modulators, i.e., compounds which bind receptor site topologically distinct from orthosteric sites, exhibit number advantages. They are more selective, safer and display ceiling effect prevents overdosing. modulators dopamine D2 potential drugs against psychiatric neurological diseases, such as schizophrenia Parkinson’s disease. In this review, an insightful summary current research on presented, ranging their pharmacology structural aspects ligand-receptor interactions to synthesis.

Language: Английский

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Dopamine D₃/D₂ Receptor Ligands Based on Cariprazine for the Treatment of Psychostimulant Use Disorders That May Be Dual Diagnosed with Affective Disorders

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(3), P. 1809 - 1834

Published: Jan. 20, 2023

Highly selective dopamine D3 receptor (D3R) partial agonists/antagonists have been developed for the treatment of psychostimulant use disorders (PSUD). However, none reached clinic due to insufficient potency/efficacy or potential cardiotoxicity. Cariprazine, an FDA-approved drug schizophrenia and bipolar disorder, is a high-affinity D3R agonist (Ki = 0.22 nM) with 3.6-fold selectivity over homologous D2 (D2R). We hypothesized that compounds are moderately D3R/D2R-selective may be effective PSUD. By systematically modifying parent molecule, we discovered agonists/antagonists, as measured in bioluminescence resonance energy transfer (BRET)-based assays, high affinities 0.14–50 moderate (<100-fold) D2R. Cariprazine two lead analogues, 13a 13e, decreased cocaine self-administration (FR2; 1–10 mg/kg, i.p.) rats, suggesting modest D3R/D2R treating PSUD potentially comorbidities other affective disorders.

Language: Английский

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Blockade of the Dopamine D3 Receptor Attenuates Opioids-Induced Addictive Behaviours Associated with Inhibiting the Mesolimbic Dopamine System

Neuroscience Bulletin, Journal Year: 2023, Volume and Issue: 39(11), P. 1655 - 1668

Published: April 11, 2023

Language: Английский

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Development of novel tools for dissection of central versus peripheral dopamine D2-like receptor signaling in dysglycemia

Diabetes, Journal Year: 2024, Volume and Issue: 73(9), P. 1411 - 1425

Published: June 13, 2024

Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and periphery are key modulators of metabolism. Moreover, disruption receptor signaling is implicated dysglycemia. Yet, respective metabolic contributions CNS versus peripheral receptors, including D2 (D2R) D3 (D3R) remain poorly understood. To address this, we developed new pharmacological tools, agonists with diminished delayed blood-brain barrier capability, to selectively manipulate D2R/D3R periphery. We designated bromocriptine methiodide (BrMeI), a quaternary analog agonist diabetes drug bromocriptine, as our lead compound based on preservation binding functional efficacy. then used BrMeI unmodified dissect relative treating Systemic administration unrestricted access targets, significantly improved insulin sensitivity glucose tolerance obese, dysglycemic mice vivo. In contrast, improvements were attenuated when was restricted either through intracerebroventricular or via BrMeI. Our findings demonstrate that coordinated actions required for correcting Ultimately, development first-generation drugs designed target provides blueprint dissecting mechanisms DA paves way novel strategies treat

Language: Английский

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The selective D3-Receptor antagonist VK4-116 effectively treats behavioral inflexibility in rats caused by self-administration and withdrawal from cocaine

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 5, 2023

Abstract Chronic psychostimulant use can cause long lasting changes to neural and cognitive function that persist even after periods of abstinence. As cocaine users transition from drug abstinence, a parallel hyperactivity hypoactivity has been found in orbitofrontal-striatal glucose metabolism, striatal D2/D3 receptor activity. Targeting these pharmacologically, using highly selective dopamine D3 (D 3 R) antagonists partial agonists, shown significant promise reducing drug-taking, attenuating relapse animal models opioid disorder. However, much less attention focused on treating inflexible potentially maladaptive non-drug behaviors following chronic use. Here we tested the D R antagonist VK4-116 as treatment for long-term behavioral inflexibility abstinent male female rats with prior history Rats were first trained self-administer (0.75 mg/kg/reinforcer) or sucrose liquid (10%, .04 mL/reinforcer) 2 weeks (FR1 schedule, max 60 reinforcers hrs/ day), followed by 4 Cognitive flexibilities then assessed sensory preconditioning (SPC) learning paradigm. given an (15 mg/kg, i.p.) vehicle 30 mins each SPC training session, thus creating four drug-treatment groups: sucrose-vehicle, sucrose-VK4-116, cocaine-vehicle, cocaine-VK4-116. The control groups (sucrose-vehicle, sucrose-VK4-116) demonstrated evidence flexible behavior, whereas (cocaine-vehicle) disrupted behavior. Remarkably, mitigated this deficit cocaine-VK4-116 group, demonstrating levels comparable groups. These preclinical findings demonstrate antagonists, particularly VK4-116, show pharmacological negative consequences

Language: Английский

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