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Expert Opinion on Therapeutic Patents Jun 2022Compelling evidence identified D3 dopamine receptor (D3R) as a suitable target for therapeutic intervention on CNS-associated disorders, cancer, and other conditions.... (Review)
Review
INTRODUCTION
Compelling evidence identified D3 dopamine receptor (D3R) as a suitable target for therapeutic intervention on CNS-associated disorders, cancer, and other conditions. Several efforts have been made toward developing potent and selective ligands for modulating signaling pathways operated by these GPCRs. The rational design of D3R ligands endowed with a pharmacologically relevant profile has traditionally not encountered much support from computational methods due to a very limited knowledge of the receptor structure and of its conformational dynamics. Recent progress in structural biology will change this state of affairs in the next decade.
AREAS COVERED
This review provides an overview of the recent (2014-2020) patent literature on novel classes of D3R ligands developed within the framework of CNS-related diseases, cancer, and additional conditions. When possible, an in-depth description of both and generated data is presented. New therapeutic applications of known molecules with activity at D3R are discussed.
EXPERT OPINION
Building on current knowledge, future D3R-focused drug discovery campaigns will be propelled by a combination of unprecedented availability of structural information with advanced computational and analytical methods. The design of D3R ligands with the sought activity, efficacy, and selectivity profile will become increasingly more streamlined.
Topics: Humans; Ligands; Patents as Topic; Receptors, Dopamine D3
PubMed: 35235753
DOI: 10.1080/13543776.2022.2049240 -
Journal of Neuroscience Research Dec 2019Dopamine signaling in the striatum is critical for a variety of behaviors including movement, behavioral flexibility, response to reward and many forms of learning.... (Review)
Review
Dopamine signaling in the striatum is critical for a variety of behaviors including movement, behavioral flexibility, response to reward and many forms of learning. Alterations to dopamine transmission contribute to pathological features of many neurological diseases, including Huntington's disease (HD). HD is an autosomal dominant genetic disorder caused by a CAG repeat expansion in the Huntingtin gene. The striatum is preferentially degenerated in HD, and this region receives dopaminergic input from the substantia nigra. Studies of HD patients and genetic rodent models have shown changes to levels of dopamine and its receptors in the striatum, and alterations in dopamine receptor signaling and modulation of other neurotransmitters, notably glutamate. Throughout his career, Dr. Michael Levine's research has furthered our understanding of dopamine signaling in the striatum of healthy rodents and HD mouse models. This review will focus on the work of his group and others in elucidating alterations to striatal dopamine signaling that contribute to pathophysiology in HD mouse models, and how these findings relate to human HD studies. We will also discuss current and potential therapeutic interventions for HD that target the dopamine system, and future research directions for this field.
Topics: Animals; Cerebral Cortex; Corpus Striatum; Disease Models, Animal; Dopamine; Glutamic Acid; Humans; Huntingtin Protein; Huntington Disease; Neurons; Receptors, Dopamine; Signal Transduction; Substantia Nigra
PubMed: 31304622
DOI: 10.1002/jnr.24495 -
Dopamine Receptors and the Kidney: An Overview of Health- and Pharmacological-Targeted Implications.Biomolecules Feb 2021The dopaminergic system can adapt to the different physiological or pathological situations to which the kidneys are subjected throughout life, maintaining homeostasis... (Review)
Review
The dopaminergic system can adapt to the different physiological or pathological situations to which the kidneys are subjected throughout life, maintaining homeostasis of natriuresis, extracellular volume, and blood pressure levels. The role of renal dopamine receptor dysfunction is clearly established in the pathogenesis of essential hypertension. Its associations with other pathological states such as insulin resistance and redox balance have also been associated with dysfunction of the dopaminergic system. The different dopamine receptors (D1-D5) show a protective effect against hypertension and kidney disorders. It is essential to take into account the various interactions of the dopaminergic system with other elements, such as adrenergic receptors. The approach to therapeutic strategies for essential hypertension must go through the blocking of those elements that lead to renal vasoconstriction or the restoration of the normal functioning of dopamine receptors. D1-like receptors are fundamental in this role, and new therapeutic efforts should be directed to the restoration of their functioning in many patients. More studies will be needed to allow the development of drugs that can be targeted to renal dopamine receptors in the treatment of hypertension.
Topics: Animals; Blood Pressure; Diabetes Mellitus; Dopamine; Essential Hypertension; Glomerular Filtration Rate; Homeostasis; Humans; Hyperinsulinism; Kidney; Kidney Diseases; Oxidative Stress; Rats; Receptors, Dopamine; Vasoconstriction
PubMed: 33578816
DOI: 10.3390/biom11020254 -
Expert Opinion on Pharmacotherapy 2023Comorbidity of substance use disorder (SUD) with schizophrenia, referred to as dual disorder (DD), significantly increases morbidity and mortality compared to... (Review)
Review
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.
Topics: Humans; Schizophrenia; Dopamine; Receptors, Dopamine D3; Receptors, Dopamine D2; Substance-Related Disorders
PubMed: 37817489
DOI: 10.1080/14656566.2023.2266359 -
Life Sciences Nov 2022Dopamine receptors have been extensively studied in the mammalian brain and spinal cord, as dopamine is a vital determinant of bodily movement, cognition, and overall... (Review)
Review
Dopamine receptors have been extensively studied in the mammalian brain and spinal cord, as dopamine is a vital determinant of bodily movement, cognition, and overall behavior. Thus, dopamine receptor antagonist antipsychotic drugs are commonly used to treat multiple psychiatric disorders. Although less discussed, these receptors are also expressed in other peripheral organ systems, such as the kidneys, eyes, gastrointestinal tract, and cardiac tissue. Consequently, therapies for certain psychiatric disorders which target dopamine receptors could have unidentified consequences on certain functions of these peripheral tissues. The existence of an intrinsic dopaminergic system in the human heart remains controversial and debated within the literature. Therefore, this review focuses on literature related to dopamine receptors within cardiac tissue, specifically dopamine receptor 3 (D3R), and summarizes the current state of knowledge while highlighting areas of research which may be lacking. Additionally, recent findings regarding crosstalk between D3R and dopamine receptor 1 (D1R) are examined. This review discusses the novel concept of understanding the role of the loss of function of D3R may play in collagen accumulation and cardiac fibrosis, eventually leading to heart failure.
Topics: Animals; Antipsychotic Agents; Dopamine; Dopamine Agonists; Dopamine Antagonists; Fibrosis; Humans; Mammals; Receptors, Dopamine D1; Receptors, Dopamine D3
PubMed: 36041503
DOI: 10.1016/j.lfs.2022.120918 -
Clinical Science (London, England :... Sep 2023Exercise has been recommended as a nonpharmaceutical therapy to treat insulin resistance (IR). Previous studies showed that dopamine D1-like receptor agonists, such as...
Exercise has been recommended as a nonpharmaceutical therapy to treat insulin resistance (IR). Previous studies showed that dopamine D1-like receptor agonists, such as fenoldopam, could improve peripheral insulin sensitivity, while antipsychotics, which are dopamine receptor antagonists, increased susceptibility to Type 2 diabetes mellitus (T2DM). Meanwhile, exercise has been proved to stimulate dopamine receptors. However, whether the dopamine D1 receptor (D1R) is involved in exercise-mediated amelioration of IR remains unclear. We found that the D1-like receptor antagonist, SCH23390, reduced the effect of exercise on lowering blood glucose and insulin in insulin-resistant mice and inhibited the contraction-induced glucose uptake in C2C12 myotubes. Similarly, the opposite was true for the D1-like receptor agonist, fenoldopam. Furthermore, the expression of D1R was decreased in skeletal muscles from streptozotocin (STZ)- and high-fat intake-induced T2DM mice, accompanied by increased D1R phosphorylation, which was reversed by exercise. A screening study showed that G protein-coupled receptor kinase 4 (GRK4) may be the candidate kinase for the regulation of D1R function, because, in addition to the increased GRK4 expression in skeletal muscles of T2DM mice, GRK4 transgenic T2DM mice exhibited lower insulin sensitivity, accompanied by higher D1R phosphorylation than control mice, whereas the AAV9-shGRK4 mice were much more sensitive to insulin than AAV9-null mice. Mechanistically, the up-regulation of GRK4 expression caused by increased reactive oxygen species (ROS) in IR was ascribed to the enhanced expression of c-Myc, a transcriptional factor of GRK4. Taken together, the present study shows that exercise, via regulation of ROS/c-Myc/GRK4 pathway, ameliorates D1R dysfunction and improves insulin sensitivity.
Topics: Animals; Mice; Diabetes Mellitus, Type 2; Fenoldopam; Insulin; Insulin Resistance; Muscle, Skeletal; Reactive Oxygen Species; Receptors, Dopamine D1
PubMed: 37622333
DOI: 10.1042/CS20230664 -
European Journal of Pharmacology Dec 2021Dopamine (DA) is an important modulator in nociception and analgesia. Spinal DA receptors are involved in descending modulation of the nociceptive transmission. Genetic...
Dopamine (DA) is an important modulator in nociception and analgesia. Spinal DA receptors are involved in descending modulation of the nociceptive transmission. Genetic variations within DA neurotransmission have been associated with altered pain sensitivity and development of chronic pain syndromes. The variant rs6277 in dopamine receptor 2 a (drd2a) has been associated with a decreased D receptor availability and increased nociception. The aim of this study is to further characterize the role of DA neurotransmission in nociception and the anti-nociceptive function of drd2a. The phenotype caused by rs6277 was modelled in zebrafish larvae using morpholino's and the effect on nociception was tested using a validated behavioural assay. The anti-nociceptive role of drd2a was tested using pharmacological intervention of D agonist Quinpirole. The experiments demonstrate that a decrease in drd2a expression results in a pro-nociceptive behavioural phenotype (P = 0.016) after a heat stimulus. Furthermore, agonism of drd2a with agonist Quinpirole (0.2 μM) results in dose-dependent anti-nociception (P = 0.035) after a heat stimulus. From these results it is concluded that the dopamine receptor drd2a is involved in anti-nociceptive behaviour in zebrafish. The model allows further screening and testing of genetic variation and treatment involved in nociception.
Topics: Animals; Behavior, Animal; Dopamine; Hot Temperature; Models, Animal; Morpholinos; Nociception; Quinpirole; Receptors, Dopamine D2; Synaptic Transmission; Zebrafish
PubMed: 34555394
DOI: 10.1016/j.ejphar.2021.174517 -
Progress in Molecular Biology and... 2023This chapter describes the physiological significance of dopamine receptor endocytosis and the consequence of the receptor signaling. Endocytosis of dopamine receptors...
This chapter describes the physiological significance of dopamine receptor endocytosis and the consequence of the receptor signaling. Endocytosis of dopamine receptors is regulated by many components such as clathrin, β-arrestin, caveolin, and Rab family proteins. The dopamine receptors escape from lysosomal digestion, and their recycling occurs rapidly, reinforcing the dopaminergic signal transduction. In addition, the pathological impact of the receptors interacting with specific proteins has been the focus of much attention. Based on this background, this chapter provides an in-depth understanding of the mechanisms of molecules interacting with dopamine receptors and discusses the potential pharmacotherapeutic targets for α-synucleinopathies and neuropsychiatric disorders.
Topics: Humans; Receptors, Dopamine; Signal Transduction; Endocytosis; Brain; beta-Arrestins
PubMed: 36813367
DOI: 10.1016/bs.pmbts.2022.09.005 -
Nature Communications Dec 2023Neuromodulatory signaling via G protein-coupled receptors (GPCRs) plays a pivotal role in regulating neural network function and animal behavior. The recent development...
Neuromodulatory signaling via G protein-coupled receptors (GPCRs) plays a pivotal role in regulating neural network function and animal behavior. The recent development of optogenetic tools to induce G protein-mediated signaling provides the promise of acute and cell type-specific manipulation of neuromodulatory signals. However, designing and deploying optogenetically functionalized GPCRs (optoXRs) with accurate specificity and activity to mimic endogenous signaling in vivo remains challenging. Here we optimize the design of optoXRs by considering evolutionary conserved GPCR-G protein interactions and demonstrate the feasibility of this approach using two Drosophila Dopamine receptors (optoDopRs). These optoDopRs exhibit high signaling specificity and light sensitivity in vitro. In vivo, we show receptor and cell type-specific effects of dopaminergic signaling in various behaviors, including the ability of optoDopRs to rescue the loss of the endogenous receptors. This work demonstrates that optoXRs can enable optical control of neuromodulatory receptor-specific signaling in functional and behavioral studies.
Topics: Animals; Receptors, Dopamine; Receptors, G-Protein-Coupled; Signal Transduction; GTP-Binding Proteins; Drosophila
PubMed: 38114457
DOI: 10.1038/s41467-023-43970-0 -
Neuroscience Letters Aug 2020Dopamine D2-like receptors (D2) mediate various effects of dopamine. Characterizing the structural and functional regions can contribute to understanding the mechanism...
PURPOSE
Dopamine D2-like receptors (D2) mediate various effects of dopamine. Characterizing the structural and functional regions can contribute to understanding the mechanism of biological effects of dopamine.
METHODS
A large scale phylogeny was utilized to construct a comprehensive dataset of D2 receptor, the evolutionary conserved residues were calculated at both super-family and sub-family (included human D2clade) levels, and then 3D structure of human D2 receptor (DRD2) was modeled to evaluate the significance of these conserved residues and motifs linked with structural stability, genetic variants, functional activation, protein interaction and drug binding.
RESULTS
All the drug binding sites and important protein-complex binding motifs showed evolutionary super-family conservation. However, genetic variants linked to different diseases all belonged to sub-family conservation. The extra cellular loop (ECL3) domain consisted of both super-family and sub-family conserved residues.
CONCLUSIONS
Sub-family conserved residues probably play a vital role in the incidence and progression of diseases.
Topics: Amino Acid Sequence; Animals; Biological Evolution; Humans; Phylogeny; Protein Conformation; Receptors, Dopamine D2
PubMed: 32454148
DOI: 10.1016/j.neulet.2020.135081