Dopamine D&lt;sub&gt;3&lt;/sub&gt; Agonists in the Treatment of Parkinson&amp;#39;s Disease

Das, Banibrata; Modi, Gyan; Dutta, Aloke K.

doi:10.2174/156802661510150328223428

Cited by 29 publications

(23 citation statements)

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“…These efforts have generally involved a hybrid drug design in which the agonist compound is linked to a known D 2 R/D 3 R antagonist fragment via a linker region. The theory being that the agonist headgroup would interact with the primary orthosteric binding pocket while the antagonist fragment would interact with a secondary binding pocket of the D 3 R, conferring D 3 R selectivity [98]. Through this method, several compounds have been synthesized and evaluated for both binding affinity and functional activity.…”

Section: D2r and D3r Selective Agonistsmentioning

confidence: 99%

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Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds

Moritz

Free

Sibley

2018

Cellular Signalling

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Compounds that target D2-like dopamine receptors (DRs) are currently used as therapeutics for several neuropsychiatric disorders including schizophrenia (antagonists) and Parkinson's disease (agonists). However, as the DR and DR subtypes are highly homologous, creating compounds with sufficient subtype-selectivity as well as drug-like properties for therapeutic use has proved challenging. This review summarizes the progress that has been made in developing DR- or DR-selective antagonists and agonists, and also describes the experimental conditions that need to be considered when determining the selectivity of a given compound, as apparent selectivity can vary widely depending on assay conditions. Future advances in this field may take advantage of currently available structural data to target alternative secondary binding sites through creating bivalent or bitopic chemical structures. Alternatively, the use of high-throughput screening techniques to identify novel scaffolds that might bind to the DR or DR in areas other than the highly conserved orthosteric site, such as allosteric sites, followed by iterative medicinal chemistry will likely lead to exceptionally selective compounds in the future. More selective compounds will provide a better understanding of the normal and pathological functioning of each receptor subtype, as well as offer the potential for improved therapeutics.

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Section: D2r and D3r Selective Agonistsmentioning

confidence: 99%

“…Dutta et al have also investigated the pramipexole scaffold as a source of D 3 R-selective agonists [98, 102-116]. The compound D-264 (Fig.…”

Section: D2r and D3r Selective Agonistsmentioning

confidence: 99%

Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds

Moritz

Free

Sibley

2018

Cellular Signalling

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“…Parkinson's disease (PD), characterized by the loss of dopaminergic neurons in the substantia nigra, is the second most common age-related neurodegenerative disorder [1]. To date, dopamine replacement and pharmacological treatments were frequently applied for symptomatic therapies in order to slow the neurodegenerative process [2]. However, despite huge contributions to clinical treatment, the efficiency was not satisfactory due to the various adverse effects [3].…”

Section: Introductionmentioning

confidence: 99%

Aberrant expression of microRNA-132-3p and microRNA-146a-5p in Parkinson’s disease patients

2020

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Parkinson’s disease (PD) is an age-related neurodegenerative disorder which is assessed based on the motor symptoms. A number of microRNAs (miRNAs) are dysregulated and involved in the pathogenesis or development of PD. However, no confirmed markers are used for the early detection of PD. The present study aimed to elucidate the potential two miRNAs (miR-132-3p and miR-146-5p) as novel markers for early PD diagnosis. In the present study, the expression levels of miR-132-3p and miR-146-5p in serum samples from 82 patients with PD and 44 healthy volunteers were measured by reverse transcription-quantitative polymerase chain reaction. Furthermore, the correlation analysis was performed between aberrant miRNAs and Braak staging, Part V of the Unified Parkinson’s Disease Rating Scale (UPDRS-V; the modified Hoehn and Yahr staging of PD) and Part III of the UPDRS-III. Subsequently, the receiver–operating characteristic (ROC) curve results of miR-132-3p and miR-146-5p from healthy volunteers for PD prediction and from severe PD patients were assessed. From the results it was observed that miR-132-3p and miR-146a-5p expressions were significantly decreased in the serum samples of patients with PD compared to those in the healthy volunteers. Moreover, the expressions of miR-132-3p and miR-146a-5p showed a dramatic decrease in severe PD patients as compared to the normal PD patients. Meanwhile, miR-132-3p and miR-146-5p expressions were negatively correlated with Braak staging (r = −0.45, P < 0.0001; r = −0.51, P < 0.0001), UPDRS-III (r = −0.55, P < 0.0001; r = −0.51, P < 0.0001) and UPDRS-V scores (r = − 0.46, P < 0.0001; r = −0.45, P < 0.0001) in PD patients. The area under the curve (AUC) results of miR-132-3p and miR-146a-5p in discriminating PD patients from the healthy controls were 0.7325 (95% CI = 0.6400–0.8251) and 0.7295 (95% CI = 0.3658–0.8232). Moreover, the AUC results of miR-132-3p and miR-146-5p concerning discriminating severe PD patients from normal PD patients were 0.8175 (95% CI = 0.7229–0.9121) and 0.7921 (95% CI = 0.6937–0.8905). In other words, both miR-132-3p and miR-146a-5p may function as promising biomarkers for early diagnosis of PD.

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“…Die Beobachtung motorischer Komplikationen nach Gabe von Levodopa [9] führte zur Entwicklung der Dopamin-Agonisten, da man sich von der selektiven Stimulation insbesondere der D2und D3-Rezeptoren eine positive Wirkung auf die Parkinson-Symptome erhoffte, ohne das Risiko motorischer Komplikationen [10,11]. In der Tat treten diese Nebenwirkungen unter Dopamin-Agonisten seltener auf, jedoch nicht in dem ursprünglich erhofften Ausmaß, sodass die Parkinson-Therapie hinsichtlich der Abwägung Levodopa versus Dopamin-Agonisten eine Neubewertung erfahren hat [12,13].…”

Section: Merkeunclassified

Grundlagen und Stellenwert der COMT- und MAO-B-Inhibitoren in der Therapie des idiopathischen Parkinson-Syndroms

Woitalla¹,

Krüger²,

Lorenzl³

et al. 2020

Fortschr Neurol Psychiatr

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ZusammenfassungCOMT- und MAO-B-Hemmer gehören neben den Dopamin-Agonisten und Levodopa zu den etablierten Pharmaka zur Behandlung des idiopathischen Parkinson-Syndroms (IPS). Die MAO-B-Hemmer Selegilin und Rasagilin entfalten auch in der Monotherapie einen symptomatischen Therapieeffekt, während Safinamid und COMT-Hemmer nur zur Kombinationstherapie mit Levodopa zugelassen sind. Beide Substanzklassen verlängern die Wirkdauer von Levodopa und optimieren die Wirkung der Therapie. Klinisch messbar resultiert eine Verlängerung der ON-Zeit. Der Einsatz von MAO-B-Inhibitoren erfolgte in der Vergangenheit auch unter der Vorstellung einer neuroprotektiven Wirkung. Trotz der aufgrund experimenteller Daten postulierten Wirkung ließ sich dieser Effekt in klinischen Studien bislang nicht zweifelsfrei belegen.

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Dopamine D<sub>3</sub> Agonists in the Treatment of Parkinson's Disease

Cited by 29 publications

References 0 publications

Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds

Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds

Aberrant expression of microRNA-132-3p and microRNA-146a-5p in Parkinson’s disease patients

Grundlagen und Stellenwert der COMT- und MAO-B-Inhibitoren in der Therapie des idiopathischen Parkinson-Syndroms

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