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Current Topics in Behavioral... 2023Before 1990, the multiplicity of dopamine receptors beyond D1 and D2 had remained a controversial concept, despite its substantial clinical implications, at a time when...
Before 1990, the multiplicity of dopamine receptors beyond D1 and D2 had remained a controversial concept, despite its substantial clinical implications, at a time when it was widely accepted that dopamine interacted with only two receptor subtypes, termed D1 and D2, differing one from the other by their pharmacological specificity and opposite effects on adenylyl cyclase. It was also generally admitted that the therapeutic efficacy of antipsychotics resulted from blockade of D2 receptors. Thanks to molecular biology techniques, the D3 receptor could be characterized as a distinct molecular entity having a restricted anatomical gene expression and different signaling, which could imply peculiar functions in controlling cognitive and emotional behaviors. Due to the structural similarities of D2 and D3 receptors, the search for D3-selective compounds proved to be difficult, but nevertheless led to the identification of fairly potent and in vitro and in vivo selective compounds. The latter permitted to confirm a role of D3 receptors in motor functions, addiction, cognition, and schizophrenia, which paved the way for the development of new drugs for the treatment of psychiatric disorders.
Topics: Humans; Receptors, Dopamine D3; Receptors, Dopamine D2; Signal Transduction; Antipsychotic Agents; Dopamine
PubMed: 35467293
DOI: 10.1007/7854_2022_315 -
Mini Reviews in Medicinal Chemistry 2015The crystal structures of the D3 dopamine receptor and several other G-protein coupled receptors (GPCRs) were published in recent times. Those 3D structures are used by... (Review)
Review
The crystal structures of the D3 dopamine receptor and several other G-protein coupled receptors (GPCRs) were published in recent times. Those 3D structures are used by us and other scientists as a template for the homology modeling and ligand docking analysis of related GPCRs. Our main scientific interest lies in the field of pharmacologically active N-arylpiperazines that exhibit antipsychotic and/or antidepressant properties, and as such are dopaminergic and serotonergic receptor ligands. In this short review article we are presenting synthesis and biological data on the new N-arylpipereazine as well our results on molecular modeling of the interactions of those N-arylpiperazines with the model of D2 dopamine receptors. To obtain that model the crystal structure of the D3 dopamine receptor was used. Our results show that the N-arylpiperazines binding site consists of two pockets: one is the orthosteric binding site where the N-arylpiperazine part of the ligand is docked and the second is a non-canonical accessory binding site for N-arylpipereazine that is formed by a second extracellular loop (ecl2) of the receptor. Until now, the structure of this receptor region was unresolved in crystal structure analyses of the D3 dopamine receptor. To get a more complete picture of the ligand - receptor interaction, DFT quantum mechanical calculations on N-arylpiperazine were performed and the obtained models were used to examine those interactions.
Topics: Binding Sites; Humans; Molecular Structure; Piperazines; Quantum Theory; Receptors, Dopamine D2
PubMed: 25723457
DOI: 10.2174/138955751512150731112448 -
International Journal of Molecular... Aug 2021Protein-protein interactions between G protein-coupled receptors (GPCRs) can augment their functionality and increase the repertoire of signaling pathways they regulate....
Protein-protein interactions between G protein-coupled receptors (GPCRs) can augment their functionality and increase the repertoire of signaling pathways they regulate. New therapeutics designed to modulate such interactions may allow for targeting of a specific GPCR activity, thus reducing potential for side effects. Dopamine receptor (DR) heteromers are promising candidates for targeted therapy of neurological conditions such as Parkinson's disease since current treatments can have severe side effects. To facilitate development of such therapies, it is necessary to identify the various DR binding partners. We report here a new interaction partner for DRD and DRD, the orphan receptor G protein-coupled receptor 143 (GPR143), an atypical GPCR that plays multiple roles in pigment cells and is expressed in several regions of the brain. We previously demonstrated that the DRD/ DRD antagonist pimozide also modulates GPR143 activity. Using confocal microscopy and two FRET methods, we observed that the DRs and GPR143 colocalize and interact at intracellular membranes. Furthermore, co-expression of wildtype GPR143 resulted in a 57% and 67% decrease in DRD and DRD activity, respectively, as determined by β-Arrestin recruitment assay. GPR143-DR dimerization may negatively modulate DR activity by changing affinity for dopamine or delaying delivery of the DRs to the plasma membrane.
Topics: Dopamine; Eye Proteins; Humans; Membrane Glycoproteins; Mutation; Protein Binding; Protein Interaction Domains and Motifs; Receptors, Dopamine D2; Receptors, Dopamine D3; Signal Transduction; beta-Arrestins
PubMed: 34361094
DOI: 10.3390/ijms22158328 -
Pflugers Archiv : European Journal of... Jun 2023The activation of beige fat and muscle tissues is an interesting and encouraging target for therapeutic intervention in obesity owing to their remarkable lipolytic...
The activation of beige fat and muscle tissues is an interesting and encouraging target for therapeutic intervention in obesity owing to their remarkable lipolytic activity and energy-consuming futile cycles. This study examined the effect of dopamine receptor D4 (DRD4) on lipid metabolisms as well as UCP1- and ATP-dependent thermogenesis in Drd4-silenced 3T3-L1 adipocytes and C2C12 muscle cells. Silencing of Drd4, followed by quantitative real-time PCR, immunoblot analysis, immunofluorescence, and staining methods, were applied to evaluate the effects of DRD4 on diverse target genes and proteins of both cells. The findings showed that DRD4 was expressed in the adipose and muscle tissues of normal and obese mice. Furthermore, the knockdown of Drd4 upregulated the expression of brown adipocyte-specific genes and proteins while downregulating lipogenesis and the adipogenesis marker proteins. Drd4 silencing also upregulated the expression of key signaling molecules involved in ATP-dependent thermogenesis in both cells. This was further elucidated by mechanistic studies showing that a Drd4 knockdown mediates UCP1-dependent thermogenesis via the cAMP/PKA/p38MAPK pathway in 3T3-L1 adipocytes and UCP1-independent thermogenesis via the cAMP/SLN/SERCA2a pathway in C2C12 muscle cells. In addition, siDrd4 also mediates myogenesis via the cAMP/PKA/ERK1/2/Cyclin D3 pathway in C2C12 muscle cells. Silencing of Drd4 promotes β3-AR-dependent browning in 3T3-L1 adipocytes and α1-AR/SERCA-based thermogenesis through an ATP-consuming futile process in C2C12 muscle cells. Understanding the novel functions of DRD4 on adipose and muscle tissues in terms of its ability to enhance energy expenditure and regulate whole-body energy metabolism will aid in developing novel obesity intervention techniques.
Topics: Animals; Mice; 3T3-L1 Cells; Adenosine Triphosphate; Adipocytes, Brown; Adipose Tissue, Brown; Muscle Cells; Obesity; Receptors, Dopamine; Receptors, Dopamine D4; Thermogenesis; Uncoupling Protein 1
PubMed: 37103560
DOI: 10.1007/s00424-023-02816-w -
Journal of Neurophysiology Jul 2022Abnormalities of auditory steady-state responses (ASSRs) and the effects of antipsychotic drugs on ASSRs have been investigated in patients with schizophrenia. It is...
Abnormalities of auditory steady-state responses (ASSRs) and the effects of antipsychotic drugs on ASSRs have been investigated in patients with schizophrenia. It is presumed that drugs do not directly affect ASSRs because its abnormalities are associated with schizophrenia. Therefore, to investigate the direct effect of drugs on ASSRs, we established an ASSR evaluation system for common marmosets in a naïve state. Dopamine D1 receptor stimulation (SKF-81297, 2 mg/kg ip) significantly increased evoked power (EP) at 40 Hz. The phase locking factor (PLF) was increased significantly at 20, 30, 40, and 80 Hz. However, administration of a dopamine D1 receptor antagonist (SCH-39166, 0.3 mg/kg ip) resulted in a significant decrease in EP and PLF at 30 Hz. Dopamine D2 receptor stimulation (quinpirole, 1 mg/kg im) tended to increase EP and induced power (IP) at all frequencies, and a significant difference was observed at 30 Hz IP. There was no change in PLF at all frequencies. In addition, dopamine D2 receptor blockade (raclopride, 3 mg/kg ip) reduced EP and PLF at 30 Hz. Subcutaneous administration of the serotonin dopamine antagonist, risperidone (0.3 mg/kg), tended to increase IP and decrease PLF, but not significantly. Taken together, it is possible to compare the differences in the mode of action of drugs on ASSRs using naïve nonhuman primates. We measured the effects of dopamine receptor-related compounds on ASSR in marmosets. D1 receptor stimulation increased the phase locking factor (PLF) and evoked power (EP), and reduced the induced power (IP). D2 receptor stimulation increased the IP. D1 and D2 receptor blockers reduced the PLF and EP at 30 Hz. Different modes of action of various drugs related to psychiatric disorders were evaluated by administering antipsychotic drugs to naïve marmosets.
Topics: Acoustic Stimulation; Animals; Antipsychotic Agents; Callithrix; Dopamine Antagonists; Evoked Potentials, Auditory; Humans; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 35583977
DOI: 10.1152/jn.00147.2022 -
Challenges in the development of dopamine D2- and D3-selective radiotracers for PET imaging studies.Journal of Labelled Compounds &... Mar 2018The dopamine D2-like receptors (ie, D2/3 receptors) have been the most extensively studied CNS receptor with Positron Emission Tomography (PET). The 3 different... (Review)
Review
The dopamine D2-like receptors (ie, D2/3 receptors) have been the most extensively studied CNS receptor with Positron Emission Tomography (PET). The 3 different radiotracers that have been used in these studies are [ C]raclopride, [ F]fallypride, and [ C]PHNO. Because these radiotracers have a high affinity for both dopamine D2 and D3 receptors, the density of dopamine receptors in the CNS is reported as the D2/3 binding potential, which reflects a measure of the density of both receptor subtypes. Although the development of D2- and D3-selective PET radiotracers has been an active area of research for many years, this by and large presents an unmet need in the area of translational PET imaging studies. This article discusses some of the challenges that have inhibited progress in this area of research and the current status of the development of subtype selective radiotracers for imaging D3 and D2 dopamine receptors with PET.
Topics: Ligands; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 28857231
DOI: 10.1002/jlcr.3558 -
Neuropsychopharmacologia Hungarica : a... Jun 2021Dopamine D3 receptors belong to the dopamine D2-like receptor family, which also includes D2 and D4 receptors. These receptors have limited anatomical distribution and...
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).
Topics: Antipsychotic Agents; Bipolar Disorder; Humans; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia
PubMed: 34342419
DOI: No ID Found -
Hormones and Behavior Jan 2021Dopamine signaling mediates the formation of some types of social relationships, including reproductive pair bonds in the socially monogamous prairie vole (Microtus...
Dopamine signaling mediates the formation of some types of social relationships, including reproductive pair bonds in the socially monogamous prairie vole (Microtus ochrogaster). In addition to these pair bonds with mates, prairie voles demonstrate selective preferences for familiar same-sex peers. The dependence of peer relationships on dopamine signaling has not been tested, and the mechanisms supporting these relationships may differ from those underlying pair bonds. We examined the effects of pharmacological manipulations of dopamine signaling on peer partner preference and socially conditioned place preference in female prairie voles. Haloperidol blockade of dopamine receptors at multiple doses did not alter selective preferences for familiar same-sex partners, suggesting that dopamine neurotransmission is not necessary for the formation of prairie vole peer relationships, unlike mate relationships. Dopamine receptor agonist apomorphine facilitated peer partner preferences under conditions normally insufficient for partner preference formation; however, in the absence of effects from blockade, it is difficult to distinguish between a role for dopamine in partner preference formation and the generally rewarding properties of a dopamine agonist. Prairie voles exhibited socially conditioned place preferences for new but not long-term same-sex peers, and these preferences were not blocked by haloperidol. These results suggest that prairie vole peer relationships are less dependent on dopamine signaling than pair bonds, while still being rewarding. The data support distinct roles of dopamine and motivation in prairie vole peer relationships relative to mate relationships, suggesting that reproductive bonds are mediated differently from non-reproductive ones.
Topics: Animals; Arvicolinae; Dopamine; Dopamine Agonists; Female; Male; Motivation; Pair Bond; Peer Group; Receptors, Dopamine; Reward; Sexual Behavior, Animal; Signal Transduction; Social Behavior
PubMed: 33152338
DOI: 10.1016/j.yhbeh.2020.104876 -
Molecules (Basel, Switzerland) Jan 2024The design and development of hybrid compounds as a new class of drug candidates remains an excellent opportunity to improve the pharmacological properties of drugs...
The design and development of hybrid compounds as a new class of drug candidates remains an excellent opportunity to improve the pharmacological properties of drugs (including enzymatic stability, efficacy and pharmacokinetic and pharmacodynamic profiles). In addition, considering various complex diseases and/or disorders, the conjugate chemistry approach is highly acceptable and justified. Opioids have long been recognized as the most potent analgesics and serve as the basic pharmacophore for potent hybrid compounds that may be useful in pain management. However, a risk of tolerance and physical dependence exists. Since dopamine receptors have been implicated in the aforementioned adverse effects of opioids, the construction of a hybrid with dual action at opioid and dopamine receptors is of interest. Herein, we present nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation results for LENART01, an opioid-ranatensin hybrid peptide. Apart from molecular docking, protein-ligand interactions were also assessed in vitro using a receptor binding assay, which proved LENART01 to be bound to mu-opioid and dopamine receptors, respectively.
Topics: Analgesics, Opioid; Bombesin; Dopamine; Molecular Dynamics Simulation; Molecular Docking Simulation; Receptors, Dopamine; Opioid Peptides; Magnetic Resonance Spectroscopy
PubMed: 38202853
DOI: 10.3390/molecules29010272 -
Methods in Molecular Biology (Clifton,... 2019S100B is a dimeric EF-hand protein that undergoes a calcium-induced conformational change and interacts with a wide range of proteins to modulate their functions. The...
S100B is a dimeric EF-hand protein that undergoes a calcium-induced conformational change and interacts with a wide range of proteins to modulate their functions. The dopamine D2 receptor is one potential S100B binding partner that may play a key role in neurological processing. In this chapter, we describe the use of NMR spectroscopy to examine the interaction between calcium-bound S100B and the third intracellular loop (IC3) from the dopamine D2 receptor. We provide details that allow the strength of the interaction (K ) between the two proteins to be determined and the IC3 site of interaction on the structure of S100B to be identified. Both these characteristics can be identified from a single series of nondestructive experiments.
Topics: Binding Sites; Calcium; Humans; Kinetics; Magnetic Resonance Spectroscopy; Models, Molecular; Protein Binding; Protein Conformation; Receptors, Dopamine D2; S100 Calcium Binding Protein beta Subunit
PubMed: 30710282
DOI: 10.1007/978-1-4939-9030-6_20