The chronic unpredictable mild stress (CUMS) Paradigm: Bridging the gap in depression research from bench to bedside

Brain Research, Journal Year: 2024, Volume and Issue: 1843, P. 149123 - 149123

Published: Nov. 1, 2024

Language: Английский

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Presynaptic and Postsynaptic Mesolimbic Dopamine D3 Receptors Play Distinct Roles in Cocaine Versus Opioid Reward in Mice

Biological Psychiatry, Journal Year: 2024, Volume and Issue: 96(9), P. 752 - 765

Published: June 3, 2024

Language: Английский

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A highly D3R-selective and efficacious partial agonist (S)-ABS01-113 compared to its D3R-selective antagonist enantiomer (R)-ABS01-113 as potential treatments for opioid use disorder

Neuropsychopharmacology, Journal Year: 2022, Volume and Issue: 47(13), P. 2309 - 2318

Published: July 25, 2022

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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Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D₃ (D₃R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(15), P. 10304 - 10341

Published: July 19, 2023

A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D3 (D3R) antagonist/partial agonists with optimized physicochemical properties was designed and synthesized. Combining in vitro cell-based on-target/off-target affinity screening, silico computer-aided drug design, BRET functional assays, we identified structural scaffolds that achieved high agonist/antagonist potencies for MOR D3R, respectively, improving the dopamine subtype selectivity (e.g., D3R over D2R) significantly enhancing central nervous system multiparameter optimization scores predicted blood–brain barrier permeability. We substituted trans-(2S,4R)-pyrrolidine trans-phenylcyclopropyl amine as key dopaminergic moieties tethered these to different scaffolds, derived from TRV130 (3) or loperamide (6). The lead compounds 46, 84, 114, 121 have potential producing analgesic effects through partial agonism reduced opioid-misuse liability via antagonism. Moreover, peripherally limited derivatives could therapeutic indications inflammation neuropathic pain.

Language: Английский

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The dopamine 3 receptor as a candidate biomarker and therapeutic for opioid use disorder

Addiction Biology, Journal Year: 2024, Volume and Issue: 29(2)

Published: Jan. 28, 2024

Here, we present recent studies suggesting that specific DRD3 single nucleotide polymorphisms (SNPs, e.g. rs324029 and rs2654754) might serve as prognostic biomarkers for opioid use disorder (OUD). Additionally, preclinical with novel dopamine 3 receptor (D3R) partial agonists antagonists have been evaluated candidate OUD therapeutics shown a reduced risk of cardiovascular toxicity compared the original D3R antagonist. From these findings, argue SNPs could diagnostic tool assessing more research is warranted examining safe effective therapeutic target treating OUD.

Language: Английский

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AM6527, a neutral CB1 receptor antagonist, suppresses opioid taking and seeking, as well as cocaine seeking in rodents without aversive effects

Neuropsychopharmacology, Journal Year: 2024, Volume and Issue: 49(11), P. 1678 - 1688

Published: April 10, 2024

Preclinical research has demonstrated the efficacy of CB1 receptor (CB1R) antagonists in reducing drug-taking behavior. However, clinical trials with rimonabant, a CB1R antagonist inverse agonist profile, failed due to severe adverse effects, such as depression and suicidality. As result, efforts have shifted towards developing novel neutral without an profile for treating substance use disorders. Here, we assessed AM6527, antagonist, addiction animal models. Our findings revealed that AM6527 did not affect cocaine self-administration under fixed-ratio reinforcement schedules but dose-dependently inhibited it progressive-ratio schedules. Additionally, heroin both oral sucrose schedule, well cocaine- or heroin-triggered reinstatement drug-seeking behavior rats. chronic administration five consecutive days significantly only during initial two days, indicating tolerance development. Notably, produce rewarding aversive effects by itself classical electrical intracranial self-stimulation conditioned place preference tests. optical (oICSS) maintained optogenetic stimulation midbrain dopamine neurons DAT-cre mice, rimonabant dopamine-dependent oICSS Together, these suggest effectively reduces seeking behaviors rimonabant-like effects. Thus, warrants further investigation potential pharmacotherapy opioid

Language: Английский

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Arrestin-3 Agonism at Dopamine D3 Receptors Defines a Subclass of Second-Generation Antipsychotics That Promotes Drug Tolerance

Biological Psychiatry, Journal Year: 2023, Volume and Issue: 94(7), P. 531 - 542

Published: March 15, 2023

Second-generation antipsychotics (SGAs) are frontline treatments for serious mental illness. Often, individual patients benefit only from some SGAs and not others. The mechanisms underlying this unpredictability in treatment efficacy remain unclear. All bind the dopamine D

Language: Английский

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ESG‐1‐60 and ESG‐1‐61: Novel dopamine D₃ receptor‐preferring partial agonists/antagonists that inhibit cocaine taking and seeking in rodents

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 27, 2025

Abstract Background and Purpose Preclinical studies suggest that highly selective dopamine D 3 receptor (D R) antagonists or partial agonists hold promise for treating substance use disorders. However, their limited effectiveness in reducing cocaine self‐administration is a major drawback. This study investigated whether cariprazine receptor‐preferring agonist) its analogues ESG‐1‐60 ESG‐1‐61 have enhanced efficacy cocaine‐taking cocaine‐seeking behaviour. Experimental Approach In vitro BRET experiments were used to characterize the functional efficacies of analogues. Intravenous reinstatement models evaluate Optical intracranial self‐stimulation (oICSS) procedures assessed effects on dopamine‐dependent Open‐field locomotion, oral sucrose conditioned place‐preference potential unwanted side effects. Key Results assays indicated are agonists, while antagonist/inverse agonist. All three compounds inhibited under both fixed‐ratio progressive‐ratio reinforcement schedules reduced cocaine‐induced drug‐seeking behaviour male female rats. The did not alter locomotor but suppressed intake oICSS. Cariprazine produced significant place aversion, not. Chronic administration self‐administration. Conclusions Implications Novel effective cocaine‐seeking, various conditions. warrants further investigation as new pharmacotherapy disorder it these lacks behavioural

Language: Английский

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Emerging Therapeutics in the Treatment of Substance Use Disorders: A Focus on GLP-1 Receptor Agonists, D3R Antagonists, and CRF Antagonists

Journal of Integrative Neuroscience, Journal Year: 2025, Volume and Issue: 24(4)

Published: April 24, 2025

The prevalence and rising use of alcohol, opioids, stimulants have led to substance disorders (SUDs) that are a significant public health challenge. Traditional treatments offer some benefit; however, they often limited by efficacy, side effects, accessibility, highlighting the urgent need for novel therapeutics. This review explores current literature surrounding three different classes treatments: glucagon-like peptide-1 (GLP-1) receptor agonists, dopamine D3 (D3R) antagonists, corticotropin-releasing factor (CRF) antagonists. These therapeutics collectively target aspects addiction process, such as stress relapse prevention, reward modulation, reduction drug-seeking behavior, leading combined multifaceted approach treating SUDs. includes preclinical clinical evidence supporting these therapies, their potential reduce prevent opioid, stimulant use. Despite potentially promising findings treatments, further research is necessary fully understand mechanisms, optimize application, confirm efficacy in settings.

Language: Английский

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