Development and Characterization of Novel Selective, Non-Basic Dopamine D2 Receptor Antagonists for the Treatment of Schizophrenia.

The dopamine D2 receptor, which belongs to the family of G protein-coupled receptors (GPCR), is an important and well-validated drug target in the field of medicinal chemistry due to its wide distribution, particularly in the central nervous system, and involvement in the pathomechanism of many disorders thereof. Schizophrenia is one of the most frequent diseases associated with disorders in dopaminergic neurotransmission, and in which the D2 receptor is the main target for the drugs used. In this work, we aimed at discovering new selective D2 receptor antagonists with potential antipsychotic activity. Twenty-three compounds were synthesized, based on the scaffold represented by the D2AAK2 compound, which was discovered by our group. This compound is an interesting example of a D2 receptor ligand because of its non-classical binding to this target. Radioligand binding assays and SAR analysis indicated structural modifications of D2AAK2 that are possible to maintain its activity. These findings were further rationalized using molecular modeling. Three active derivatives were identified as D2 receptor antagonists in cAMP signaling assays, and the selected most active compound 17 was subjected to X-ray studies to investigate its stable conformation in the solid state. Finally, effects of 17 assessed in animal models confirmed its antipsychotic activity in vivo.

Dopamine D3 Receptors: From Bench to Bedside.

Dopamine D3 receptors belong to the dopamine D2-like receptor family, which also includes D2 and D4 receptors. These receptors have limited anatomical distribution and are mainly expressed in brain regions and pathways that typically mediate the actions of antipsychotic drugs and medication used against Parkinson's disease (PD). The development of cariprazine, the fi rst D2/D3 partial agonist with prominent affi nity and preferential activity at D3 receptors over other dopamine receptor subtypes was a landmark that provided new insights into the neurochemical and physiological functions of D3 receptors. Preclinical studies and clinical trials provided evidence for the clinical advantages of cariprazine in the treatment of schizophrenia and bipolar disorder. Cariprazine became the fi rst antipsychotic drug approved for the treatment of manic, mixed and depressive episodes in bipolar I disorder. Antagonism of D3 receptors may play a role in ameliorating symptoms of levodopa-induced dyskinesia and psychosis in PD patients treated with levodopa/carbidopa. Accordingly, D3 receptors constitute attractive targets for developing novel drugs for the improved treatment of different psychiatric and neurological disorders. (Neuropsychopharmacol Hung 2021; 23(2): 272-280).

Discovery of CNS-Like D3R-Selective Antagonists Using 3D Pharmacophore Guided Virtual Screening.

The dopamine D3 receptor is an important CNS target for the treatment of a variety of neurological diseases. Selective dopamine D3 receptor antagonists modulate the improvement of psychostimulant addiction and relapse. In this study, five and six featured pharmacophore models of D3R antagonists were generated and evaluated with the post-hoc score combining two survival scores of active and inactive. Among the Top 10 models, APRRR215 and AHPRRR104 were chosen based on the coefficient of determination (APRRR215: R²training = 0.80; AHPRRR104: R²training = 0.82) and predictability (APRRR215: Q²test = 0.73, R²predictive = 0.82; AHPRRR104: Q²test = 0.86, R²predictive = 0.74) of their 3D-quantitative structure⁻activity relationship models. Pharmacophore-based virtual screening of a large compound library from eMolecules (>3 million compounds) using two optimal models expedited the search process by a 100-fold speed increase compared to the docking-based screening (HTVS scoring function in Glide) and identified a series of hit compounds having promising novel scaffolds. After the screening, docking scores, as an adjuvant predictor, were added to two fitness scores (from the pharmacophore models) and predicted Ki (from PLSs of the QSAR models) to improve accuracy. Final selection of the most promising hit compounds were also evaluated for CNS-like properties as well as expected D3R antagonism.

Dopamine D3 Receptor in Parkinson Disease: A Prognosis Biomarker and an Intervention Target.

Parkinson disease (PD) dementia, pathologically featured as nigrostriatal dopamine (DA) neuronal loss with motor and non-motor manifestations, leads to substantial disability and economic burden. DA therapy targets the DA D3 receptor (D3R) with high affinity and selectivity. The pathological involvement of D3R is evidenced as an effective biomarker for disease progression and DA agnostic interventions, with compensations of increased DA, decreased aggregates of α-synuclein (α-Syn), enhanced secretion of brain-derived neurotrophic factors (BDNF), attenuation of neuroinflammation and oxidative damage, and promoting neurogenesis in the brain. D3R also interacts with D1R to reduce PD-associated motor symptoms and alleviate the side effects of levodopa (L-DOPA) treatment. We recently found that DA D2 receptor (D2R) density decreases in the late-stage PDs, while high D3R or DA D1 receptor (D1R) + D3R densities in the postmortem PD brains correlate with survival advantages. These new essential findings warrant renewed investigations into the understanding of D3R neuron populations and their cross-sectional and longitudinal regulations in PD progression.

The Role of Dopamine D3 Receptors in Tobacco Use Disorder: A Synthesis of the Preclinical and Clinical Literature.

Tobacco smoking is a significant cause of preventable morbidity and mortality globally. Current pharmacological approaches to treat tobacco use disorder (TUD) are only partly effective and novel approaches are needed. Dopamine has a well-established role in substance use disorders, including TUD, and there has been a long-standing interest in developing agents that target the dopaminergic system to treat substance use disorders. Dopamine has 5 receptor subtypes (DRD1 to DRD5). Given the localization and safety profile of the dopamine receptor D3 (DRD3), it is of therapeutic potential for TUD. In this chapter, the preclinical and clinical literature investigating the role of DRD3 in processes relevant to TUD will be reviewed, including in nicotine reinforcement, drug reinstatement, conditioned stimuli and cue-reactivity, executive function, and withdrawal. Similarities and differences in findings from the animal and human work will be synthesized and findings will be discussed in relation to the therapeutic potential of targeting DRD3 in TUD.

Current Perspectives on Selective Dopamine D3 Receptor Antagonists/Partial Agonists as Pharmacotherapeutics for Opioid and Psychostimulant Use Disorders.

Over three decades of evidence indicate that dopamine (DA) D3 receptors (D3R) are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders (SUD). The expectation that a selective D3R antagonist/partial agonist would be efficacious for the treatment of SUD is based on the following key observations. First, D3R are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and ventral pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse produces neuroadaptations in the D3R system. Third, the synthesis and characterization of highly potent and selective D3R antagonists/partial agonists have further strengthened the role of the D3R in SUD. Based on extensive preclinical and preliminary clinical evidence, the D3R shows promise as a target for the development of pharmacotherapies for SUD as reflected by their potential to (1) regulate the motivation to self-administer drugs and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, drug-associated environmental cues, or stress. The availability of PET ligands to assess clinically relevant receptor occupancy by selective D3R antagonists/partial agonists, the definition of reliable dosing, and the prospect of using human laboratory models may further guide the design of clinical proof of concept studies. Pivotal clinical trials for more rapid progression of this target toward regulatory approval are urgently required. Finally, the discovery that highly selective D3R antagonists, such as R-VK4-116 and R-VK4-40, do not adversely affect peripheral biometrics or cardiovascular effects alone or in the presence of oxycodone or cocaine suggests that this class of drugs has great potential in safely treating psychostimulant and/or opioid use disorders.

The role of the D3 dopamine receptor and its partial agonist cariprazine in patients with schizophrenia and substance use disorder.

INTRODUCTION: Comorbidity of substance use disorder (SUD) with schizophrenia, referred to as dual disorder (DD), significantly increases morbidity and mortality compared to schizophrenia alone. A dopaminergic dysregulation seems to be a common pathophysiological basis of the comorbidity. AREAS COVERED: This article reports the current evidence on the role of dopamine dysregulations in DD, the pharmacological profile of cariprazine, a partial agonist of D3 and D2 dopamine receptors, and first clinical observations that may support its usefulness in the therapy of DD. PubMed/MEDLINE was searched for the keywords 'cariprazine,' 'schizophrenia,' 'dual disorder,' 'dopamine,' and 'dopamine receptor.' Preclinical and clinical studies, and reviews published in English were retrieved. EXPERT OPINION: Although the management of DD remains challenging, and the evidence for pharmacologic treatments is still unsatisfactory, cariprazine may be a candidate medication in DD due to its unique mechanism of action. Preliminary clinical experiences suggest that cariprazine has both antipsychotic and anticraving properties and should be considered early in patients with DD.

The position statement of the Working Group of the Polish Psychiatric Association on the use of D2/D3 dopamine receptor partial agonists in special populations. / Stanowisko grupy roboczej Polskiego Towarzystwa Psychiatrycznego na temat stosowania czesciowych agonistów receptorów dopaminowych D2/D3 w populacjach szczególnych.

D2/D3 dopamine receptor partial agonists (aripiprazole, brexpiprazole, cariprazine) are increasingly often used in the treatment of mental disorders due to a more favourable tolerability profile as compared to other antipsychotics. The article presents the position statement on the use of these drugs in the treatment of special populations: people with comorbid somatic diseases, people over 65 years of age, including those with dementia, children and adolescents, pregnant and breastfeeding women. The position statement was developed by the panel of experts appointedby the Executive Board of the Polish Psychiatric Association consisting of people experienced in the treatment of patients with mental disorders. The evaluation included the analysis of literature databases and information obtained from summaries of product characteristics, as well as reports and registers on the safety of the three evaluated drugs. D2/D3 dopamine receptor partial agonists can be used in the treatment of people who must be provided with the highest safety standards of the therapy. It results from their low risk of producing side effects, such as weight gain, metabolic disorders, akathisia, extrapyramidal symptoms, increased prolactin levels, prolongation of QTinterval in ECG, sedation and anticholinergic effects. Since dopamine receptor partial agonists are available for arelatively short time, there is less information on their use in pregnant women than for other antipsychotics.

The position statement of the Working Group of the Polish Psychiatric Association on the use of D2/D3 dopamine receptor partial agonists in the treatment of mental disorders. / Stanowisko grupy roboczej Polskiego Towarzystwa Psychiatrycznego na temat stosowania czesciowych agonistów receptorów dopaminowych D2/D3 w leczeniu zaburzen psychicznych.

Aripiprazole, cariprazine and brexpiprazole are antipsychotic drugs (APD) whose action is associated with partial agonism at the dopamine D2/D3 receptors. They are increasingly more widely used in clinical practice, also off-label. The aim of this article is to present the current state of knowledge on the use of these drugs in the treatment of mental disorders. The position statement was developed by the panel of experts appointedby the Executive Board of the Polish Psychiatric Association, consisting of individuals with many years of experience in treating patients with mental disorders. The evaluation included the analysis of literature databases (Medline, Embase, Cochrane) and information obtained from metaanalyses and summaries of product characteristics. A key property of D2/D3 partial agonists is that they display diverse effects on dopamine pathways: (a) blockade of mesolimbic signalling that is overactive in the acute phase of schizophrenia and mania, (b) stimulation of mesocortical pathways with an improvement (or at least with no deterioration) of cognitive functions and negative symptoms, (c) no blockade of the tuberoinfundibular pathway and, consequently, low risk of increased prolactin secretion, (d) no blockade of nigrostriatal pathway and, consequently, low risk of extrapyramidal symptoms. Selective profile of action and intrinsic activity at dopamine D2 (aripiprazole > brexpiprazole) and D3 (cariprazine) receptors in combination with the lack of antihistamine and anticholinergic properties make aripiprazole, brexpiprazole and cariprazine different form other APD in terms of their safety and tolerability. This is the reason for the increasing use of these drugs in the treatment of schizophrenia and mood disorders, and in the case of aripiprazole also in obsessive-compulsive, autism-spectrum and tic disorders.

COMT by DRD3 Epistatic Interaction in Modulating Behaviors in Children with ADHD: A Pharmaco-Dynamic Behavioral Approach.

OBJECTIVE: Examining the joint effect of two functional variants in two dopamine-related genes (DRD3 and COMT) on ADHD-relevant behaviors under three experimental conditions (EC). METHOD: 362 children with ADHD were assessed by parents and teachers during a week of baseline evaluation, followed by 1 week of MPH and placebo, administered in a double-blind crossover design. RESULTS: Statistically significant 3-way (DRD3-by-COMT-by-EC; p = .004) and 2-way interactions (COMT by EC; p = .002) were observed on Conners'-Teachers scores. Children with the COMT Met/Met genotype had lower scores at baseline and on placebo compared to the other genotype groups. Furthermore, stratifying the children according to their COMT genotypes helped to detect statistically significant and biologically meaningful effects of DRD3 genotype. CONCLUSIONS: These findings suggest that COMT and DRD3 genetic variants may together play a role in ADHD symptomatology and response to treatment through gene-gene interaction.

Dopamine D3 receptor-based medication development for the treatment of opioid use disorder: Rationale, progress, and challenges.

Opioid abuse and related overdose deaths continue to rise in the United States, contributing to the current national opioid crisis. Although several opioid-based pharmacotherapies are available (e.g., methadone, buprenorphine, naloxone), they show limited effectiveness in long-term relapse prevention. In response to the opioid crisis, the National Institute on Drug Abuse proposed a list of pharmacological targets of highest priority for medication development for the treatment of opioid use disorders (OUD). Among these are antagonists of dopamine D3 receptors (D3R). In this review, we first review recent progress in research of the dopamine hypothesis of opioid reward and abuse and then describe the rationale and recent development of D3R ligands for the treatment of OUD. Herein, an emphasis is placed on the effectiveness of newly developed D3R antagonists in the animal models of OUD. These new drug candidates may also potentiate the analgesic effects of clinically used opioids, making them attractive as adjunctive medications for pain management and treatment of OUD.