Editorial

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Open AccessEditorial

Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases

by Philippe De Deurwaerdère and Abdeslam Chagraoui

Biomolecules 2021, 11(5), 713; https://doi.org/10.3390/biom11050713 - 11 May 2021

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Biomolecules has launched a Special Issue entitled “Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases [...] Full article

(This article belongs to the Special Issue Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases)

Research

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12 pages, 2895 KiB

Open AccessArticle

Interaction of Ligands for PET with the Dopamine D3 Receptor: In Silico and In Vitro Methods

by Chia-Ju Hsieh, Aladdin Riad, Ji Youn Lee, Kristoffer Sahlholm, Kuiying Xu, Robert R. Luedtke and Robert H. Mach

Biomolecules 2021, 11(4), 529; https://doi.org/10.3390/biom11040529 - 02 Apr 2021

Cited by 8 | Viewed by 2709

Abstract

[¹⁸F]Fallypride and [¹⁸F]Fluortriopride (FTP) are two different PET radiotracers that bind with sub-nanomolar affinity to the dopamine D3 receptor (D₃R). In spite of their similar D₃ affinities, the two PET ligands display very different properties for [...] Read more.

[¹⁸F]Fallypride and [¹⁸F]Fluortriopride (FTP) are two different PET radiotracers that bind with sub-nanomolar affinity to the dopamine D3 receptor (D₃R). In spite of their similar D₃ affinities, the two PET ligands display very different properties for labeling the D₃R in vivo: [¹⁸F]Fallypride is capable of binding to D₃R under “baseline” conditions, whereas [¹⁸F]FTP requires the depletion of synaptic dopamine in order to image the receptor in vivo. These data suggest that [¹⁸F]Fallypride is able to compete with synaptic dopamine for binding to the D₃R, whereas [¹⁸F]FTP is not. The goal of this study was to conduct a series of docking and molecular dynamic simulation studies to identify differences in the ability of each molecule to interact with the D₃R that could explain these differences with respect to competition with synaptic dopamine. Competition studies measuring the ability of each ligand to compete with dopamine in the β-arrestin assay were also conducted. The results of the in silico studies indicate that FTP has a weaker interaction with the orthosteric binding site of the D₃R versus that of Fallypride. The results of the in silico studies were also consistent with the IC50 values of each compound in the dopamine β-arrestin competition assays. The results of this study indicate that in silico methods may be able to predict the ability of a small molecule to compete with synaptic dopamine for binding to the D₃R. Full article

(This article belongs to the Special Issue Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases)

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13 pages, 1619 KiB

Open AccessArticle

by Hana Brozka, Daniela Alexova, Dominika Radostova, Martina Janikova, Branislav Krajcovic, Štěpán Kubík, Jan Svoboda and Ales Stuchlik

Biomolecules 2021, 11(1), 84; https://doi.org/10.3390/biom11010084 - 11 Jan 2021

Cited by 3 | Viewed by 2274

Abstract

Quinpirole (QNP) sensitization is a well-established model of stereotypical checking relevant to obsessive-compulsive disorder. Previously, we found that QNP-treated rats display deficits in hippocampus-dependent tasks. The present study explores the expression of immediate early genes (IEG) during QNP-induced stereotypical checking in the hippocampus, [...] Read more.

Quinpirole (QNP) sensitization is a well-established model of stereotypical checking relevant to obsessive-compulsive disorder. Previously, we found that QNP-treated rats display deficits in hippocampus-dependent tasks. The present study explores the expression of immediate early genes (IEG) during QNP-induced stereotypical checking in the hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and medial prefrontal cortex (mPFC). Adult male rats were injected with QNP (0.5 mg/mL/kg; n = 15) or saline (n = 14) daily for 10 days and exposed to an arena enriched with two objects. Visits to the objects and the corners of the arena were recorded. QNP-treated rats developed an idiosyncratic pattern of visits that persisted across experimental days. On day 11, rats were exposed to the arena twice for 5 min and sacrificed. The expression of IEGs Arc and Homer1a was determined using cellular compartment analysis of temporal activity by fluorescence in situ hybridization. IEG-positive nuclei were counted in the CA1 area of the hippocampus, ACC, OFC, and mPFC. We found significantly fewer IEG-positive nuclei in the CA1 in QNP-treated rats compared to controls. The overlap between IEG expressing neurons was comparable between the groups. We did not observe significant differences in IEG expression between QNP treated and control rats in ACC, OFC, and mPFC. In conclusion, treatment of rats with quinpirole decreases plasticity-related activity in the hippocampus during stereotypical checking. Full article

(This article belongs to the Special Issue Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases)

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9 pages, 287 KiB

Open AccessArticle

Smoking Genes: A Case–Control Study of Dopamine Transporter Gene (SLC6A3) and Dopamine Receptor Genes (DRD1, DRD2 and DRD3) Polymorphisms and Smoking Behaviour in a Malay Male Cohort

by Abu Bakar Ruzilawati, Md Asiful Islam, Siti Khariem Sophia Muhamed and Imran Ahmad

Biomolecules 2020, 10(12), 1633; https://doi.org/10.3390/biom10121633 - 03 Dec 2020

Cited by 6 | Viewed by 3936

Abstract

Dopamine receptor and dopamine transporter genes polymorphisms have been associated with cigarette smoking behaviour in different populations. The aim of this case–control study was to evaluate polymorphisms in the dopamine transporter gene (SLC6A3 (rs27072)) and the dopamine receptor genes (DRD1 (rs686), [...] Read more.

Dopamine receptor and dopamine transporter genes polymorphisms have been associated with cigarette smoking behaviour in different populations. The aim of this case–control study was to evaluate polymorphisms in the dopamine transporter gene (SLC6A3 (rs27072)) and the dopamine receptor genes (DRD1 (rs686), DRD2 (rs1800497) and DRD3 (rs7653787)) and their contribution to smoking behaviour in a Malay male population. We identified 476 participants over the age of 18 years comprising 238 smokers and 238 non-smokers. Information such as age, height, weight, body mass index, systolic and diastolic blood pressures, marital status, and smoking status of close family members were taken. For the genetic study, we genotyped four genes (SLC6A3 (rs27072), DRD1 (rs686), DRD2 (rs1800497) and DRD3 (rs7653787)) using the polymerase chain reaction–restriction fragment length polymorphism method and further confirmed our findings with sequencing. Dopamine receptor genes (DRD1, DRD2 and DRD3) were found to be associated with smoking behaviour in a Malay male population. The dopamine transporter gene (SLC6A3) did not show this association. Significant differences were observed between smokers’ and non-smokers’ age, systolic blood pressure, marital status and family members who smoke. Smoking behaviour is significantly influenced by genetic variations of DRD1, DRD2 and DRD3 in a Malay male population. Full article

(This article belongs to the Special Issue Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases)

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16 pages, 1777 KiB

Open AccessArticle

The Long-Acting D3 Partial Agonist MC-25-41 Attenuates Motivation for Cocaine in Sprague-Dawley Rats

by Gregory L. Powell, Mark D. Namba, Annika Vannan, John Paul Bonadonna, Andrew Carlson, Rachel Mendoza, Peng-Jen Chen, Robert R. Luetdke, Benjamin E. Blass and Janet L. Neisewander

Biomolecules 2020, 10(7), 1076; https://doi.org/10.3390/biom10071076 - 18 Jul 2020

Cited by 9 | Viewed by 2685

Abstract

The dopamine D3 receptor is a prime target for developing treatments for cocaine use disorders (CUDs). In this study, we conducted a pre-clinical investigation of the therapeutic potential of a long-acting, D3 receptor partial agonist, MC-25-41. Male rats were pre-treated with MC-25-41 (vehicle, [...] Read more.

The dopamine D3 receptor is a prime target for developing treatments for cocaine use disorders (CUDs). In this study, we conducted a pre-clinical investigation of the therapeutic potential of a long-acting, D3 receptor partial agonist, MC-25-41. Male rats were pre-treated with MC-25-41 (vehicle, 1.0, 3.0, 5.6, or 10 mg/kg, intraperitoneal (IP)) five minutes prior to tests of cocaine or sucrose intake on either a progressive ratio schedule of reinforcement or a variable interval 60 s multiple schedule consisting of 4, 15-min components with sucrose or cocaine available in alternating components. A separate cohort of rats was tested on a within-session, dose-reduction procedure to determine the effects of MC-25-41 on demand for cocaine using a behavioral economics analysis. Finally, rats were tested for effects of MC-25-41 on spontaneous and cocaine-induced locomotion. MC-25-41 failed to alter locomotion, but reduced reinforcement rates for both cocaine and sucrose on the low-effort, multiple schedule. However, on the higher-effort, progressive ratio schedule of cocaine reinforcement, MC-25-41 reduced infusions, and active lever presses at doses that did not alter sucrose intake. The behavioral economics analysis showed that MC-25-41 also increased cocaine demand elasticity compared to vehicle, indicating a reduction in consumption as price increases. Together, these results suggest that similar to other D3-selective antagonists and partial agonists, MC-25-41 reduces motivation for cocaine under conditions of high cost but has the added advantage of a long half-life (>10 h). These findings suggest that MC-25-41 may be a suitable pre-clinical lead compound for development of medications to treat CUDs. Full article

(This article belongs to the Special Issue Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases)

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Review

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34 pages, 5439 KiB

Open AccessReview

Neurobiological and Pharmacological Perspectives of D3 Receptors in Parkinson’s Disease

by Abdeslam Chagraoui, Giuseppe Di Giovanni and Philippe De Deurwaerdère

Biomolecules 2022, 12(2), 243; https://doi.org/10.3390/biom12020243 - 01 Feb 2022

Cited by 4 | Viewed by 2406

Abstract

The discovery of the D3 receptor (D3R) subtypes of dopamine (DA) has generated an understandable increase in interest in the field of neurological diseases, especially Parkinson’s disease (PD). Indeed, although DA replacement therapy with l-DOPA has provided an effective treatment for patients [...] Read more.

The discovery of the D3 receptor (D3R) subtypes of dopamine (DA) has generated an understandable increase in interest in the field of neurological diseases, especially Parkinson’s disease (PD). Indeed, although DA replacement therapy with l-DOPA has provided an effective treatment for patients with PD, it is responsible for invalidating abnormal involuntary movements, known as L-DOPA-induced dyskinesia, which constitutes a serious limitation of the use of this therapy. Of particular interest is the finding that chronic l-DOPA treatment can trigger the expression of D1R–D3R heteromeric interactions in the dorsal striatum. The D3R is expressed in various tissues of the central nervous system, including the striatum. Compelling research has focused on striatal D3Rs in the context of PD and motor side effects, including dyskinesia, occurring with DA replacement therapy. Therefore, this review will briefly describe the basal ganglia (BG) and the DA transmission within these brain regions, before going into more detail with regard to the role of D3Rs in PD and their participation in the current treatments. Numerous studies have also highlighted specific interactions between D1Rs and D3Rs that could promote dyskinesia. Finally, this review will also address the possibility that D3Rs located outside of the BG may mediate some of the effects of DA replacement therapy. Full article

(This article belongs to the Special Issue Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases)

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39 pages, 11703 KiB

Open AccessEditor’s ChoiceReview

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

by Béla Kiss, István Laszlovszky, Balázs Krámos, András Visegrády, Amrita Bobok, György Lévay, Balázs Lendvai and Viktor Román

Biomolecules 2021, 11(1), 104; https://doi.org/10.3390/biom11010104 - 14 Jan 2021

Cited by 36 | Viewed by 6466

Abstract

Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 [...] Read more.

Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy. Full article

(This article belongs to the Special Issue Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases)

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18 pages, 1509 KiB

Open AccessBrief Report

Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor

by Pramisha Adhikari, Bing Xie, Ana Semeano, Alessandro Bonifazi, Francisco O. Battiti, Amy H. Newman, Hideaki Yano and Lei Shi

Biomolecules 2021, 11(4), 570; https://doi.org/10.3390/biom11040570 - 13 Apr 2021

Cited by 8 | Viewed by 2284

Abstract

The dopamine D2/D3 receptor (D₂R/D₃R) agonists are used as therapeutics for Parkinson’s disease (PD) and other motor disorders. Selective targeting of D₃R over D₂R is attractive because of D₃R’s restricted tissue distribution with [...] Read more.

The dopamine D2/D3 receptor (D₂R/D₃R) agonists are used as therapeutics for Parkinson’s disease (PD) and other motor disorders. Selective targeting of D₃R over D₂R is attractive because of D₃R’s restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the D₂R and D₃R poses a challenge in the development of D₃R selective agonists. To address the ligand selectivity, bitopic ligands were designed and synthesized previously based on a potent D₃R-preferential agonist PF592,379 as the primary pharmacophore (PP). This PP was attached to various secondary pharmacophores (SPs) using chemically different linkers. Here, we characterize some of these novel bitopic ligands at both D₃R and D₂R using BRET-based functional assays. The bitopic ligands showed varying differences in potencies and efficacies. In addition, the chirality of the PP was key to conferring improved D₃R potency, selectivity, and G protein signaling bias. In particular, compound AB04-88 exhibited significant D₃R over D₂R selectivity, and G protein bias at D₃R. This bias was consistently observed at various time-points ranging from 8 to 46 min. Together, the structure-activity relationships derived from these functional studies reveal unique pharmacology at D₃R and support further evaluation of functionally biased D₃R agonists for their therapeutic potential. Full article

(This article belongs to the Special Issue Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases)

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