Selective Dopamine D3 Receptor Agonist Research Articles

Cortico-striatal gamma oscillations are modulated by dopamine D3 receptors in dyskinetic rats.

JOURNAL/nrgr/04.03/01300535-202504000-00031/figure1/v/2024-07-06T104127Z/r/image-tiff Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia. Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia. Currently, studies have reported increased oscillation power in cases of levodopa-induced dyskinesia. However, little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia. Furthermore, the role of the dopamine D3 receptor, which is implicated in levodopa-induced dyskinesia, in movement disorder-related changes in neural oscillations is unclear. We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson's disease. Furthermore, levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components, as well as bidirectional primary motor cortex (M1) ↔ dorsolateral striatum gamma flow. Administration of PD128907 (a selective dopamine D3 receptor agonist) induced dyskinesia and excessive gamma oscillations with a bidirectional M1 ↔ dorsolateral striatum flow. However, administration of PG01037 (a selective dopamine D3 receptor antagonist) attenuated dyskinesia, suppressed gamma oscillations and cortical gamma aperiodic components, and decreased gamma causality in the M1 → dorsolateral striatum direction. These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity, and that it has potential as a therapeutic target for levodopa-induced dyskinesia.

Multiple roles of β‐Arrestin2 in initiating and sustaining D3R‐mediated ERK1/2 phosphorylation by G protein‐biased and unbiased D3R agonists

β‐arrestins play key roles in both terminating G protein signaling and activating G protein‐independent signaling across many G protein coupled receptors (GPCRs); however, the roles of β‐arrestins in dopamine D3 receptor (D3R)‐mediated ERK phosphorylation/signaling are poorly characterized. Our previous studies showed that novel compounds SK609 and its analog SK608 are selective D3R agonists and display Gi/o biased signaling without significant recruitment of β‐arrestin2 (βarr2) compared with dopamine which can potently activate G proteins and recruit β‐arrestins. We hypothesize that βarr2 plays multiple roles in initiating and sustaining D3R‐mediated ERK1/2 phosphorylation by G protein‐biased and unbiased D3R agonists. We tested this hypothesis using neuron‐like SH‐SY5Y cells stably expressing D3R (SH‐SY5Y‐D3R cells) with βarr2 knockdown (βarr2KD) in vitro. Our results show: SK609 and SK608 or pramipexole (PRX) time‐dependently elicited both the early and late phases of mono phosphorylation of ERK1/2; SK608 or SK609 only elicited the early phase of dual phosphorylation, whereas PRX induced both the early and late phases and sustained for 1‐4 h; βarr2KD partially reduced mono ERK1/2 phosphorylation by PRX but not SK608 or SK609; βarr2KD significantly enhanced both the early and late phases of dual ERK1/2 phosphorylation by SK608 or SK609 whereas it partially reduced the early phase by PRX and completely abolished the late phase; Gi/o inhibitor PTX abolished PRX‐ or SK608 and SK609‐induced mono ERK1/2 phosphorylation and SK608‐ and SK609‐induced the early phase of dual ERK1/2 phosphorylation, whereas the early phase of dual phosphorylation by PRX was abolished but the late phase was not affected; Gbg inhibitor Galllein had no effect on PRX‐ induced dual phosphorylation of ERK1/2 but inhibited SK609‐ or SK608‐indued dual phosphorylation; PKC inhibitor Go6983 greatly reduced or completely abolished PRX‐ or SK608‐ and SK609‐induced the mono phosphorylation, and blocked SK608‐ or SK609‐induced the dual phosphorylation in SH‐SY5Y‐D3R cells. In contrast, Go6983 abolished PRX‐induced late phase of dual phosphorylation, it only partially reduced PRX‐induced early phase; PTX plus Go6983 completely abolished PRX‐ or SK608‐ and SK609‐induced mono or dual ERK1/2 phosphorylation in SH‐SY5Y‐D3R/βarr2KD cells. In summary, βarr2 not only participates in inhibiting G protein‐biased D3R agonist‐induced early and late phases of dual ERK1/2 phosphorylation and activating unbiased D3R agonists‐induced the early and late phases of the dual phosphorylation, but also is required for Gi/o‐ or PKCs‐dependent the early phase of the mono and dual ERK1/2 phosphorylation. These findings support multiple roles in which βarr2 acts as both signal terminator for G protein biased agonist‐induced ERK1/2 signaling and signal transducer for unbiased D3R agonist‐induced signaling interactions among βarr2 and Gi/o and PKCs which collaboratively regulate ERK1/2 signaling.

Correction: Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D3 receptor agonists.

Correction for 'Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D3 receptor agonists' by Yongkai Cao et al., Med. Chem. Commun., 2018, DOI: 10.1039/c8md00237a.

In vivo characterization of a novel dopamine D3 receptor agonist to treat motor symptoms of Parkinson's disease

Synthetic dopaminergic agents have found utility in treating neurological and neuropsychiatric disorders since the beginning of 19th century. The discovery of Levodopa (l-dopa) to effectively treat motor symptoms of Parkinson's disease (PD) revolutionized the therapy and remains a gold standard for treating PD. However, l-dopa therapy has been implicated in worsening of the non-motor symptoms including cognition and long-term therapy leads to plasticity and development of abnormal involuntary movements (AIMs) that are collectively called l-dopa induced dyskinesias (LID). Studies in rodents and non-human primates with PD have supported a role for dopamine D3 receptors in the etiology of both the motor symptoms and LID. We have recently developed SK609, a selective dopamine D3 receptor agonist with atypical signaling properties. In this study, we further characterized this novel small molecule using the unilateral lesioned rodent model of PD. In the forepaw stepping test paradigm, SK609 significantly improved the performance of the impaired paw and also normalized the bilateral asymmetry associated with the hemiparkinson rat. In addition, a chronic treatment of SK609 did not induce any AIMs and when used adjuvantly with l-dopa significantly reduced AIMs induced by l-dopa. Further, an optimal dose combination of SK609 with l-dopa was determined by dose dependent titrations of both SK609 and l-dopa that produced minimal AIMs and maximized the effect on improving motor symptoms. Results from this study suggest that SK609 is a novel dopaminergic agent that has the therapeutic potential to treat PD and LID.This article is part of the Special Issue entitled ‘Synaptopathy – from Biology to Therapy’.

Gradient of dopamine responsiveness to dopamine receptor agonists in subregions of the rat nucleus accumbens

The present study sought to investigate the possibility that the degree of selectivity of dopamine D3/D2 receptor agonists such as quinelorane, 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT), quinpirole and apomorphine on dopamine D3 over D2 receptor subtypes can be assessed by measuring dopamine transmission in the shell vs. core compartments of the nucleus accumbens by using microdialysis in freely moving rats. Significant reductions in dialysate dopamine levels compared to vehicle-treated animals were observed in the shell of the nucleus accumbens with 3, 10 and 30 μg/kg quinelorane, 100 μg/kg 7-OH DPAT, 25 and 100 μg/kg quinpirole, and 100 μg/kg apomorphine. In the core subregion, significant reductions in dopamine were seen at 10 and 30 μg/kg quinelorane, 25 and 100 μg/kg 7-OH-DPAT, 100 μg/kg quinpirole and 100 μg/kg apomorphine. However, a significant shell/core dichotomy could only be observed in response to the lowest dose of quinelorane (3 μg/kg) with the shell being hyper-responsive compared with the core. The present findings suggest that quinelorane is one of the most selective dopamine D3 receptor agonists based on its ability to target the shell subregion of the nucleus accumbens.

Repeated 7-OH-DPAT treatments: behavioral sensitization, dopamine synthesis and subsequent sensitivity to apomorphine and cocaine

Male Wistar rats (250-350 g) were injected (SC) daily with the putative selective dopamine D3 receptor agonist, 7-OH-DPAT (0.01, 0.10, or 1.0 g/kg) or vehicle for 10 days. Fifteen minutes after each injection, the rats were tested for locomotor activity in photocell arenas for 20 min or 2 h. In two experiments, following this subchronic treatment, all rats received a challenge injection of apomorphine (1.0 mg/kg, SC), or cocaine (10 mg/kg, IP) on day 11, and were tested for locomotor activity. In a third experiment, dopamine synthesis in striatal and mesolimbic (nucleus accumbens-olfactory turbercle) tissue was assessed following acute or chronic 7-OH-DPAT treatments by measuring the accumulation of dihydroxyphenylalanine (DOPA) after treatment with a DOPA decarboxylase inhibitor. Major findings were as follows: a) acute 7-OH-DPAT treatment produced a dose-dependent decrease in locomotor activity; b) when tested for 2 h, the 1.0 mg/kg dose of 7-OH-DPAT produced a progressively greater increase in activity across the 10 test days (i.e., behavioral sensitization); c) subchronic treatment with 7-OH-DPAT did not result in cross-sensitization to either apomorphine or cocaine; d) acute treatment with the 1.0 mg/kg dose of 7-OH-DPAT significantly decreased dopamine synthesis in both striatal and mesolimbic regions; and e) chronic 7-OH-DPAT treatments did not affect basal dopamine synthesis in either brain region. Although the behavioral effects of 7-OH-DPAT were similar to the reported effects of the D2/D3 dopamine agonist quinpirole, the effects of repeated 7-OH-DPAT treatments differed from those of quinpirole in terms of cross-sensitization and basal dopamine synthesis. These results suggest that locomotor inhibition produced by low doses of 7-OH-DPAT is not related to dopamine autoreceptor stimulation, and the development of behavioral sensitization to high doses of 7-OH-DPAT is not due to the development of dopamine autoreceptor subsensitivity.