Dopamine Receptor Agonist Research Articles

A Genetic Assessment of Dopamine Agonist-Induced Impulse Control Disorder in Patients With Prolactinoma.

Dopamine agonist (DA)-induced impulse control disorder (ICD) represents a group of behavioral disorders that are increasingly recognized in patients with prolactinoma. We aimed to examine the genetic component of the underlying mechanism of DA-induced ICD. Patients with prolactinoma receiving dopamine agonist (cabergoline) treatment were included in the study. These patients were divided into 2 groups: patients who developed ICD due to DA and patients who did not. Patients were evaluated for polymorphisms of the DRD1, DRD3, COMT, DDC, GRIN2B, TPH2, OPRK1, OPRM1, SLC6A4, SLC6A3, HTR2A genes. Of the 72 patients with prolactinoma using cabergoline, 20 were diagnosed with ICD. When patients with and without ICD were compared according to genotype frequencies, OPRK1/rs702764, DRD3/rs6280, HTR2A/rs6313, SLC6A4/rs7224199, GRIN2B/rs7301328, TPH2/rs7305115, COMT/rs4680, DRD1/rs4532 polymorphisms significantly increased in patients with DA-induced ICD. Our results show that multiple neurotransmission systems affect DA-induced ICD in patients with prolactinoma.

Inhibition of Tau Protein Aggregation Using Small Molecule Inhibitors and Immunotherapies

AbstractBackgroundTau protein aggregation is one of the biomarkers of neurodegenerative diseases and is a viable drug target. Small molecules and immunotherapies have been tested targeting tauopathies. Understanding of the inhibitor mode‐of‐action is needed in order to develop effective drugs against neurodegeneration.MethodThe full length tau protein (2N4R, 441) was used in vitro with aggregation inducers: heparin and arachidonic acid. We have used small molecule inhibitors based of dopamine receptor agonist as inhibitors of tau aggregation in vitro. The inhibition of tau aggregation was also conducted in vitro using anti‐tau antibodies. The biophysical methods including electron microscopy and fluorescence spectroscopy were used to measure inhibitor efficiency.ResultThe anti‐tau antibodies which target epitope in R1‐R4 repeat domain were most effective in inhibition aggregation. The small molecules containing catechol groups were effective aggregation inhibitors and were in micromolar range, which was similar to the efficacy of methylene blue.ConclusionThe tau aggregation was inhibited in vitro using dual approach, with small and large molecules, indicating that both strategies are viable against tauopathies. Future work will require design of multifunctional inhibitors to improve selectivity and potency.

Efficacy and safety of non-ergot dopamine-receptor agonists as an adjunct to levodopa in advanced Parkinson's disease: Anetwork meta-analysis.

Non-ergot dopamine agonists (NEDAs) have been used as an adjunct therapy to levodopa in advanced Parkinson's disease (PD) for many years. However, there is no strong evidence that a given NEDA is more potent than another. To compare and rank the efficacy, tolerability, and safety of six commonly used NEDAs as an adjunct to levodopa in advanced PD, which includes long-acting and standard formulations, a network meta-analysis was performed. The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, and Wanfang databases were searched from January 1996 to June 2022 for eligible randomized controlled trials (RCTs). Six NEDAs, including rotigotine transdermal patch, ropinirole immediate-release (IR)/prolonged-release (PR), pramipexole IR/extended-release (ER), and piribedil, were investigated. A total of 34 RCTs (7868 patients) were included in the current study. The surface under the cumulative ranking curve indicated that ropinirole PR was associated with the best improvement in Unified Parkinson's Disease Rating Scale (UPDRS)-II, UPDRS-III, and UPDRS-II + III (0.811, 0.742, and 0.827). For OFF time reduction, pramipexole IR ranked first (0.979), and ropinirole PR ranked first in OFF time responder rate (0.927). Pramipexole ER ranked first in overall withdrawals, and rotigotine transdermal patch ranked first in the incidence of adverse events (≥1 AEs). This network meta-analysis suggests six commonly used NEDAs are effective as an adjunct to levodopa in advanced PD. In comprehensive consideration of better symptomatic management, ropinirole PR may be a better choice than other NEDAs in advanced PD. Six NEDAs showed different profiles of AEs.

Spinal dopaminergic D1 and D5 receptors contribute to reserpine-induced fibromyalgia-like pain in rats

Fibromyalgia is a complex pain syndrome without a precise etiology. Reduced monoamines levels in serum and cerebrospinal fluid in fibromyalgia patients has been reported and could lead to a dysfunction of descending pain modulatory system producing the painful syndrome. This study evaluated the role of D1-like dopamine receptors in the reserpine-induced fibromyalgia-like pain model in female Wistar rats. Reserpine-treated animals were intrathecally injected with different dopamine receptors agonists and antagonists, and small interfering RNAs (siRNAs) against D1 and D5 receptor subtypes. Withdrawal and muscle pressure thresholds were assessed with von Frey filaments and the Randall-Selitto test, respectively. Expression of D1-like receptors in lumbar spinal cord and dorsal root ganglion was determined using real time polymerase chain reaction (qPCR). Reserpine induced tactile allodynia and muscle hyperalgesia. Intrathecal dopamine and D1-like receptor agonist SKF-38393 induced nociceptive hypersensitivity in naïve rats, whilst this effect was prevented by the D1-like receptor antagonist SCH-23390. Moreover, SCH-23390 induced a sex-dependent antiallodynic effect in reserpine-treated rats. Furthermore, transient silencing of D1 and D5 receptors significantly reduced reserpine-induced hypersensitivity in female rats. Reserpine slightly increased mRNA D5 receptor expression in dorsal spinal cord, but not in DRG. This work provides new insights about the involvement of the spinal dopaminergic D1/D5 receptors in reserpine-induced hypersensitivity in rats.

Partial agonists of dopamine receptors: theoretical principles of combining antipsychotics including partial agonists to treat schizophrenia

SUMMARYPartial agonists such as aripiprazole are often used in addition to a full antagonist such as amisulpride, risperidone or olanzapine in an attempt to mitigate side-effects such as sedation, hyperprolactinaemia and weight gain. However, there can be unintended consequences, including worsening of psychosis. Moreover, previous exposure to a partial agonist may impair the subsequent response to a potent antipsychotic such as haloperidol used to control symptoms of relapse. To understand the mechanisms involved, a method is needed to compare potency in the pharmacological effects of different drugs used in combinations. This article is intended to explore and explain the theoretical principles based on the dopamine hypothesis of schizophrenia. We apply the method to analyse a recently described trial in which two full antagonists (olanzapine and amisulpride) are compared individually and in combination.

FEATURES OF THE COURSE OF COVID-19 IN WOMEN WITH HYPERPROLACTINEMIA

The 2019 coronavirus pandemic is a major stressful event. In turn, stressful situations are triggers for the exacerbation of existing and activation of new diseases caused by a violation of the immune response in the human body and the development of inflammatory diseases. A stressful state causes the release of stress-mediated hormones, which in turn contributes to an increase in the level of PRL. Obviously, it is a closed circle. Therefore, the questions become relevant: 1. Can stress against the background of Covid-19 really cause an increase in the level of PRL? 2. Can Sovid-19 worsen the course of an already existing HP? Purpose: to conduct an analysis of available medical research on the peculiarities of the course of Covid-19 in women with HP, highlighting research on this topic in order to systematize new views on the diagnosis and treatment of Covid-19 against the background of already existing HP. Materials and methods. 10 articles from 2018 to 2022 with the keywords prolactin, hyperprolactinemia and Covid-19 were analyzed. Research results and their discussion. A review and analysis of a closed cohort study in which 30 men and 15 women participated and passed the Trier social stress test showed that PRL levels were significantly increased in response to a stressor [10], which could be the Covid-19 pandemic. In SARS-CoV-2, the defined receptor binding domain of the viral membrane protein uses angiotensin-converting enzyme 2 (ACE2) as a receptor for virus-host membrane fusion [2]. ACE2 regulates the activity of dopamine decarboxylase (DDC), which is responsible for the synthesis of dopamine and serotonin. Thus, SARS-CoV-2 disrupts the biosynthesis of dopamine, which leads to an increase in the level of PRL. With Covid-19, the expression of TLR4 and NF-κB is activated and increases the induction release of pro-inflammatory cytokines with the development of ALI, ARDS and cytokines with MOF. Conclusions Based on the studies described above, it can be concluded that Covid-19 inhibits the synthesis of dopamine and thus increases the level of prolactin. Also, prolactin can exhibit both
 immunostimulating and immunosuppressive, as well as pro-inflammatory and anti-inflammatory effects. Treatment with agonists of dopamine receptors can lead to deepening of depression in Covid-19. Treatment of hyperprolactinemia should be carried out with caution, because in critically ill patients who require personal support, the use of amine derivatives with DRA can cause additional vasospasm and, as a result, a rapid increase in blood pressure.

SKF83959 Attenuates Memory Impairment and Depressive-like Behavior during the Latent Period of Epilepsy via Allosteric Activation of the Sigma-1 Receptor.

Memory impairment and emotional disorder are two common clinical comorbidities in patients with epilepsy. It is imperative to develop a novel therapeutic agent or a strategy. 6-Chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is a dopamine-1 receptor agonist and sigma-1 receptor allosteric modulator, which displays the neuron-protective and anti-neuroinflammation activity. We examined the effect of SKF83959 on the memory impairment and emotional disorder in the latent period of epilepsy using the mice post-status epilepticus model. We found that SKF83959 ameliorated memory impairment and depressive-like mood, alleviated the neuron damage and the formation of gliosis in hippocampus, suppressed the rise of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, and induced nitric oxide synthase in the latent period of epilepsy. Additionally, SKF83959 significantly inhibited the activity of calcineurin and glycogen synthase kinase-3β. All of these protective actions were reversed by BD1047 (a sigma-1 receptor antagonist). In addition, the intra-hippocampus injection of ketoconazole (a dehydroepiandrosterone synthesis inhibitor) also reversed the protective activity of SKF83959. Thus, we concluded that SKF83959 ameliorated the memory impairment and depressive-like mood in epilepsy via allosterically activating the sigma-1 receptor and subsequently inhibiting the calcineurin/glycogen synthase kinase-3β pathway.

ODP311 Giant-versus Macroadenomas: Does Size Really Matter in Pituitary Somatotroph Adenomas?

Abstract Objectives Since the literature about giant (≥40 mm)pituitary somatotroph adenomas is limited to case reports, we aimed to summarize the characteristics of our giant somatotroph pituitary adenoma cohort and compare their clinical features and treatment responses with somatotroph macroadenomas. Materials and Methods This retrospective study included 16 patients (6 F/10 M) and 57 patients (29 F/28 M) with adenoma sizes ≥40 mm and 20-39 mm, respectively. The patients with <40 mm adenoma size were further divided into subgroups with adenoma size 20-29 mm (26 patients) and 30-39 mm (31 patients). Preoperative and postoperative hormone profiles, imaging and pathological findings, number of surgeries, presence of residual tumor, treatment modalities (including somatostatin receptor ligands, dopamine receptor agonists, pegvisomant, radiotherapy) and remission status were compared between groups. Results In giant somatotroph adenomas group, mean value of the preoperative maximal diameter of adenoma was 44.8±10.1 mm (range 40-80 mm). Mean age at diagnosis was 31.8±12.6 years (range 11-55). Mean preoperative GH level was 127.4±257.1 ng/mL. The highest GH level was measured as 951 ng/mL in a female patient having a giant pituitary adenoma with a maximum diameter of 50 mm. Mean baseline IGF-1 level was 2.33±1. 04×ULN (upper limit of normal) for age and sex. Mean number of surgery was 2.4±1.5 (range 1-6) and mean number of treatment modalities applied to achieve hormonal remission postoperatively was 2.1±0.9 (range 1-3). After a mean duration of follow-up of 11.2±6.5 years (range 1-21 years), hormonal remission and partial control were achieved in nine and two patients, respectively. In the group with adenoma size <40 mm, mean value of the preoperative maximal diameter of adenoma was 28.4±5.2 mm (range 20-38 mm) and mean age at diagnosis was 35.8±10.5 years (range 15-62). When we compare the groups, the number of surgeries was significantly higher in giant adenoma group in which 11 of 16 patients (68.8%) underwent repeated surgeries (p=0. 009). The rate of gross total resection tended to decrease as tumor size increases. While radiotherapy was given to 62.5% of the patients with giant adenoma, it was applied to 26.9% and 35.5% of the patients in the groups with adenoma size 20-29 mm and 30-39 mm, respectively (p=0. 068). The total number of treatment modalities applied to achieve hormonal remission postoperatively tended to be higher with increasing adenoma size, although not statistically significant (p=0. 062). Although preoperative GH and IGF-1 levels and Ki-67 index tended to be higher with increasing adenoma size, there was no statistically significant difference between the groups in terms of these variables. Hormonal remission rates were similar between groups. Conclusion Giant somatotroph adenomas require an aggressive multimodal treatment approach and advanced care to achieve sustainable hormonal remission. Presentation: No date and time listed

Potential of Therapeutic Small Molecules in Apoptosis Regulation in the Treatment of Neurodegenerative Diseases: An Updated Review.

Neurodegenerative disorders (NDs) include Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the common feature of NDs is the progressive death of specific neurons in the brain. Apoptosis is very important in developing the nervous system, nonetheless an elevated level of cell death has been observed in the case of NDs. NDs are different in terms of their neuronal vulnerability and clinical manifestations, however they have some overlapping neurodegenerative pathways. It has been demonstrated by several studies with cell lines and animal models that apoptosis has a significant contribution to make in advancing AD, ALS, HD, and PD. Numerous dying neurons were also identified in the brains of individuals with NDs and these conditions were found to be linked with substantial cell loss along with common characteristics of apoptosis including activation of caspases and cysteine-proteases, DNA fragmentation, and chromatin condensation. It has been demonstrated that several therapeutic agents including antioxidants, minocycline, GAPDH ligands, p53 inhibitors, JNK (c-Jun N-Terminal Kinase) inhibitors, glycogen synthase kinase-3 inhibitor, non-steroidal anti-inflammatory drugs, D2 dopamine receptor agonists, FK506, cell cycle inhibitors, statins, drugs targeting peroxisome proliferator-activated receptors, and gene therapy have the potential to provide protection to neurons against apoptosis. Therefore, the use of these potential therapeutic agents might be beneficial in the treatment of NDs. In this review, we have summarized the pathways that are linked with apoptotic neuronal death in the case of various NDs. We have particularly focused on the therapeutic agents that have neuroprotective properties and the potential to regulate apoptosis in NDs.

Parkinson’s disease, dopaminergic drugs and the plant world

A large proportion of drugs used for the treatment of neurological disorders relate to naturally occurring compounds, many of which are plant alkaloids. This is particularly true of Parkinson’s disease (PD). The pharmacopoeia of PD has strong botanical origins, while major discoveries about the neurochemistry of the basal ganglia came from the study of phytochemicals. This article narrates the development of pharmacotherapy for PD in terms of historically important plant-derived substances—tropane and hamala alkaloids, reserpine, levodopa, apomorphine, and ergoline dopamine receptor agonists. Alkaloids are nitrogen-containing secondary metabolic products that tend to be biologically active. They appear to be involved in plants’ adaptation to herbivorous animals, though their exact purpose and the ways in which they work are uncertain. A sizable group of alkaloids influence animal dopaminergic systems, highlighting a key biological relationship. While animals must acquire the energy that plants harness, plants need to engage with the animal attribute that they lack—movement—in order to maximize their reproductive fitness. Neuroactive flowering plant compounds have been interacting with vertebrate and invertebrate motor systems for 100 million years. A deep evolutionary connection helps to explain why the pharmacological treatment of PD is imprinted with the power of these mysterious botanical chemicals.

Piribedil in the treatment of mental and cognitive impairments in Parkinson's disease

Mental and cognitive impairments are common non-motor symptoms of Parkinson's disease (PD), which affect more than half of patients at various stages of the disease. These symptoms significantly reduce the quality of life of patients and their relatives. The article reflects the features of the pathogenesis of mental and cognitive impairments in PD, as well as the role of the dopamine receptor agonist piribedil in their correction. Piribedil, having a good safety and tolerability profile, and also, presumably, having a positive effect on such non-motor symptoms of PD as increased daytime sleepiness, depression, apathy, anhedonia and cognitive functions, can significantly improve the quality of life of patients and their adherence to therapy.

Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson’s disease

Inflammation is one of the pathogenic processes in Parkinson’s disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg−1·d−1, i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1β in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1β, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100–400 μM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated by Drd3 depletion. Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 μM) in vitro and astrocyte-specific Atg5 knockdown in vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.

Striatal mechanisms of turning behaviour following unilateral dopamine depletion in mice.

Unilateral dopamine (DA) depletion produces ipsiversive turning behaviour, and the injection of DA receptor agonists can produce contraversive turning, but the underlying mechanisms remain unclear. We conducted in vivo recording and pharmacological and optogenetic manipulations to study the role of DA and striatal output in turning behaviour. We used a video-based tracking programme while recording single unit activity in both putative medium spiny projection neurons (MSNs) and fast-spiking interneurons (FSIs) in the dorsal striatum bilaterally. Our results suggest that unilateral DA depletion reduced striatal output from the depleted side, resulting in asymmetric striatal output. Depletion systematically altered activity in both MSNs and FSIs, especially in neurons that increased firing during turning movements. Like D1 agonist SKF 38393, optogenetic stimulation in the depleted striatum increased striatal output and reversed biassed turning. These results suggest that relative striatal outputs from the two cerebral hemispheres determine the direction of turning: Mice turn away from the side of higher striatal output and towards the side of the lower striatal output.

Spectrofluorimetric and stability-indicating thin layer chromatographic methods for determination of cabergoline, a prolactin inhibitor in pharmaceuticals

Simple, Economic, and selective spectrofluorimetric and stability-indicating thin layer chromatographic (TLC) with fluorescence detection methods were developed for the determination of Cabergoline, a potent prolactin inhibitor, and long-acting dopamine receptor agonist, in bulk drug and pharmaceutical dosage forms based on its native fluorescence. Method A was based on measuring the fluorescence intensity at 338 nm after excitation at 280 nm. The measured fluorescence was directly proportional to the concentration of the drug over the range of 50.0–450.0 ng/mL with a limit of detection of 14.4 and a limit of quantification of 43.7 ng/mL. The TLC method (method B) was employed on TLC silica gel 60 F254 aluminum sheets previously exposed to concentrated (30–34 %) hydrochloric acid vapor. Ethyl acetate: n-hexane: diethylamine system with a ratio of (10: 3: 1, v/v/v) developing system was used. The retention factor (Rf) of Cabergoline was 0.58 ± 0.03. Linearity was found to be in the range of 100.0–1500.0 ng/band. The LOD and LOQ were 25.4 and 76.9 ng/band, respectively. The methods were validated successfully according to ICH guidelines.

Effects of lysophosphatidic acid on sling and clasp fibers of the human lower esophageal sphincter

Background This study aims to explore the role of lysophosphatidic acid receptors in the regulation mechanisms of contraction and relaxation of human lower esophageal sphincter. Methods Between July 2015 and March 2016, muscle strips were collected from a total of 30 patients (19 males, 11 females; mean age: 62±9.9 years; range, 52 to 68 years) who underwent an esophagectomy for mid-third esophageal carcinomas. The specimens were maintained in oxygenated Krebs solution. Muscle tension measurement technique in vitro was used to examine the effects of non-selective lysophosphatidic acid receptors agonists and antagonists, as well as selective lysophosphatidic acid receptors agonists on the clasp and sling fibers of human lower esophageal sphincter. Results The non-selective dopamine receptor agonist lysophosphatidic acid induced the contraction of the clasp and sling fibers of the human lower esophageal sphincter. The response induced by nonselective lysophosphatidic acid receptor agonist was inhibited completely by non-selective lysophosphatidic acid receptor antagonist. The selective lysophosphatidic acid 1 and 2 receptor agonist and the selective lysophosphatidic acid 3 receptor agonist induced a concentration-dependent contractile response of the clasp and sling fibers of the human lower esophageal sphincter. There was no significant difference in contraction rates between the clasp and sling fibers (p>0.05). Conclusion This study indicates that lysophosphatidic acid regulates the lower esophageal sphincter is through its receptor; the lysophosphatidic acid receptors may be involved in the contractile response of the human lower esophageal sphincter.

Excessive Daytime Sleepiness in Parkinson's Disease is Related to Functional Abnormalities in the Left Angular Gyrus.

Excessive daytime sleepiness (EDS) is acommon non-motor symptom in Parkinson's disease (PD), but its neuropathology remains elusive. Our goal is to explore the potential neural substrates of EDS in alarge sample of individuals with PD. We recruited 48PD patients with and 87PD patients without EDS. We used resting-state functional magnetic resonance imaging to compare amplitudes of low-frequency fluctuations (ALFF) between the two groups. We also explored functional connectivity (FC) between the entire brain and regions where ALFF differed between the two groups as well as FC between selected regions of interest. Age, PartIII of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) score and use of dopamine receptor agonists were treated as covariates in the comparisons. EDS was associated with significantly lower ALFF in the left angular gyrus, and ALFF in this region correlated negatively with score on the Epworth Sleepiness Scale in patients with PD. EDS was also associated with significantly lower FC between the left angular gyrus and right cerebellum, based on seed-to-voxel and inter-ROI analyses. Our results suggest that EDS in PD patients is associated with reduced spontaneous neural activity in the left angular gyrus and with reduced FC between the left angular gyrus and cerebellum. These findings may help understand and treat EDS in PD.

Abstract 5381: Combinatory effect of EZH2 inhibitor and dopamine D1 receptor agonist enhance inhibition of triple negative breast cancer cell growth

Abstract Treatment for Triple Negative Breast Cancer remains a challenge due to its aggressive behavior; poor clinical outcome and disposition to therapeutic resistance. The diverse clinical and molecular characteristics drives high level of heterogeneity in breast cancer. Overall change in the epigenome triggers oncogenic activity of enhancer of zeste homolog 2 (EZH2) causing changes in gene expression that leads to cancer progression. EZH2 is the catalytic member of the Polycomb group protein complex that provides the active site for covalent methylation reactions. High expression of EZH2 is strongly associated with aggressive TNBC phenotypes, compared to other non-TNBCs. Development of resistance to EZH2 inhibitors limit their therapeutic use. Studies have shown that dopamine receptor (DR) agonists and antagonists alter TNBC cell growth in both in vitro and in vivo models. Our objective was to investigate if a combination of a D1R agonist with an EZH2 inhibitor was effective to attenuate TNBC cell proliferation. Docking studies were performed using Schrodinger software and visualization software to determine the affinity of GSK126 and SKF38393 towards EZH2. TNBC cells were treated individually and combined with EZH2 inhibitor, GSK126, and D1 agonist SKF38393 for cell viability and immunoprecipitation. Insilco analysis using docking studies revealed that SKF38393 actively interacts in the same region where GSK126 binds to EZH2 i.e. the catalytic site. Combination treatment of TNBC cells with GSK126 and SKF38393 caused synergistic inhibition of cell viability, suppressed the H3K27 trimethylation activity, and inhibited invasion of TNBC cells. Immunoprecipitation of EZH2 in the presence of GSK126 and SKF38393 dissociated the association between EZH2, EED, and SUZ12 in MDA-MB-231 cells. We report that combination of GSK126 and SKF38393 may have an enhanced efficacy in inhibiting the catalytic function of EZH2. The combined treatment of TNBC cells with GSK126 and SKF38393 inhibit TNBC proliferation by disrupting EZH2 functions. (This work is supported by DOD: W81XWH2010065, for Eswar Shankar) Citation Format: Prem Prakash Kushwaha, Shiv Verma, Gautham Sarathy, Anmol Kumar, Sanjay Gupta, Bhuvaneswari Ramaswamy, Sarmila Majumder, Eswar Shankar. Combinatory effect of EZH2 inhibitor and dopamine D1 receptor agonist enhance inhibition of triple negative breast cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5381.

Structure-Functional Selectivity Relationship Studies on A-86929 Analogs and Small Aryl Fragments toward the Discovery of Biased Dopamine D1 Receptor Agonists.

Dopamine regulates normal functions such as movement, reinforcement learning, and cognition, and its dysfunction has been implicated in multiple psychiatric and neurological disorders. Dopamine acts through D1- (D1R and D5R) and D2-class (D2R, D3R, and D4R) receptors and activates both G protein- and β-arrestin-dependent signaling pathways. Current dopamine receptor-based therapies are used to ameliorate motor deficits in Parkinson's disease or as antipsychotic medications for schizophrenia. These drugs show efficacy for ameliorating only some symptoms caused by dopamine dysfunction and are plagued by debilitating side effects. Studies in primates and rodents have shown that shifting the balance of dopamine receptor signaling toward the arrestin pathway can be beneficial for inducing normal movement, while reducing motor side effects such as dyskinesias, and can be efficacious at enhancing cognitive function compared to balanced agonists. Several structure-activity relationship (SAR) studies have embarked on discovering β-arrestin-biased dopamine agonists, focused on D2 partial agonists, noncatechol D1 agonists, and mixed D1/D2R dopamine receptor agonists. Here, we describe an SAR study to identify novel D1R β-arrestin-biased ligands using A-86929, a high-affinity D1R catechol agonist, as a core scaffold to identify chemical motifs responsible for β-arrestin-biased activity at both D1 and D2Rs. Most of the A-86929 analogs screened were G protein-biased, but none of them were exclusively arrestin-biased. Additionally, various small-fragment molecular probes displayed weak bias toward the β-arrestin pathway. Continued in-depth SFSR (structure-functional selectivity relationship) studies informed by structure determination, molecular modeling, and mutagenesis studies will facilitate the discovery of potent and efficacious arrestin-biased dopamine receptor ligands.

Hyperprolactinemia syndrome in women: diagnosis and correction

The article is devoted to modern views on the diagnosis and treatment of hyperprolactinemia syndrome in women. Prolactinomas are the leading cause of hyperprolactinemia syndrome. The main clinical manifestations of a pathological increase in the level of prolactin are hypogonadism and galactorrhea, in some cases there are neurological symptoms, as well as psycho-emotional and asthenovegetative disorders. The publication reviews management tactics of patients with prolactinomas and pathological conditions secondary to elevated prolactin levels. Both conservative approaches to the correction of hyperprolactinemia and surgical treatment methods are described. It is noted that at present, drug therapy has priority over surgery. In the medical treatment of hyperprolactinemia, dopamine receptor agonists are used. The duration of therapy with this group of drugs is at least 2 years. The targets should be long-term normalisation of prolactin levels and a significant reduction in the size of the tumour or its absence according to the results of magnetic resonance imaging of the brain. Women with drug-resistant prolactinomas are advised to increase the dose of dopamine receptor agonists to the maximum tolerated dose before considering surgical intervention. Special attention is paid to the management of patients whose pregnancy occurred amid a pathological increase in the level of prolactin. In addition, methods for correcting drug-induced hyperprolactinemia are considered. The long list of drugs that can cause increased prolactin levels shows that the problem of hyperprolactinemia may be encountered by doctors of various specialties. The data presented in the publication are based on clinical guidelines approved by the Russian Ministry of Health and comply with the principles of evidence-based medicine.

Clinical features of hyperprolactinemia in children: modern methods of diagnosis and treatment

Hyperprolactinemia is a common endocrine disease that can be associated with significant morbidity and disability in the population. A systematic review of literature sources on the diagnosis and treatment results in patients with hyperprolactinemia, including drug-resistant micro- and macroadenomas of the pituitary gland, was carried out in order to highlight the most significant practical recommendations. The purpose of this literature review is to provide algorithms for differential diagnosis and clinical observation of patients, to compare the efficacy and side effects of drugs, surgeries, and radiation therapy in the treatment of hyperprolactinemia. Prolactinomas are the most common pituitary adenomas in older children. Their share in the structure of pituitary adenomas is about 50 %. The clinical picture depends on the age, sex of the child, volume and characteristics of tumor growth. The leading clinical manifestations of hyperprolactinemia are disorders of the reproductive system, including signs of the development of secondary hypogonadotropic hypogonadism, sexual dysfunction, psychoemotional disorders, and endocrine and metabolic disorders. The main criterion for the diagnosis of hyperprolactinemia is the concentration of prolactin in the blood serum, which is above the upper limit of the physiological norm. The primary step in the treatment of patients with pituitary macroadenoma is to control the compression effects of the tumor, including compression of the optic chiasm, followed by restoration of gonadal function. The main areas of treatment for hyperprolactinemia are restoration and maintenance of the normal function of the gonads; restoration of fertility; prevention of osteoporosis. Dopamine receptor agonists are the gold standard in the treatment of hyperprolactinemia. However, some people do not respond satisfactorily to these drugs. In this case, in the presence of pituitary tumors, in addition to drug treatment, surgery and radiation therapy are used. But surgery and radiation therapy are not the primary methods of choice for the management of patients with prolactin-secreting pituitary adenomas; first of all, preference is given to drug therapy. The prognosis of the course of prolactinomas is favorable and is based on the results of dynamic observation and the presence of markers of the aggressiveness of this adenoma.