Anti-parkinsonian activity of the adenosine A2A receptor antagonist/inverse agonist KW-6356 as monotherapy in MPTP-treated common marmosets

Ohno, Yutaro; Okita, Eri; Kawai-Uchida, Mika; Fukuda, Naoko; Shoukei, Youji; Soshiroda, Kazuhiro; Yamada, Koji; Kanda, Tomoyuki; Uchida, Shunya

doi:10.1016/j.ejphar.2023.175773

Cited by 5 publications

(3 citation statements)

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“…Moreover, increased mean of striatal A2AR availability correlated with greater severity of motor symptom severity (P = 0.02) [48]. KW-6356, a novel A2AR antagonist and inverse agonist when administered to MPTP-treated marmosets significantly reversed motor impairments [87]. Its effectiveness in suppressing PD symptoms exceeded istradefylline and did not induce such dyskinesia.…”

Section: The Effect Of A2ar Antagonism On Motor Symptoms Of Parkinson...mentioning

confidence: 98%

How can caffeine alleviate the motor symptoms of Parkinson’s disease? – the implications of adenosine 2A receptor antagonism

Wójcik,

Górny,

Chwiejczak

et al. 2024

J Educ Health Sport

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Introduction and purpose: Parkinson’s disease (PD) is the second most common neurodegenerative disease, mainly characterized by motor impairment with symptoms including rigidity, bradykinesia, rest tremor and imbalance. It develops upon degeneration of dopaminergic neurons in the substantia nigra associated with neuroinflammatory process initiated by alpha-synuclein deposits. Although, levodopa replacement therapy is the gold-standard treatment, majority of the treated patients develop dyskinesia as the side effect, resulting from altered function of dopamine receptors. It is thought that the abnormal pulsate release of dopamine can be prevented by antagonism of adenosine 2A receptors (A2ARs). Aim of the study: This review aims to outline the action mechanism of A2AR antagonism on motor performance, and thus evaluate the suggested implications of coffee consumption in PD. Material and method: The involvement of A2ARs in the pathology and treatment of PD has been analyzed based on the findings of many published studies examining the effects of A2AR modulation. Results: Blockage of A2ARs enhances the action of dopamine via D2 receptors on striatopallidal neurons, decreasing their hyperactivity, and exerts neuroprotective effect, suppressing the neuroinflammation. Conclusions: Istradefylline, being the only approved A2AR antagonist, was able to reduce total cumulative dose of levodopa, improve motor control, alleviate postural abnormalities, and provide a reduction in daily ‘off’ time experienced by patients. Recent findings suggest the effects of drinking one cup of coffee are comparable with ones obtained by the newly introduced medication, presumably via shared action mechanism by A2AR inhibition.

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Section: The Effect Of A2ar Antagonism On Motor Symptoms Of Parkinson...mentioning

confidence: 98%

How can caffeine alleviate the motor symptoms of Parkinson’s disease? – the implications of adenosine 2A receptor antagonism

Wójcik,

Górny,

Chwiejczak

et al. 2024

J Educ Health Sport

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“…When tested on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, KW-6356 demonstrated a remarkable ability to effectively reverse motor disability. Notably, its anti-parkinsonian activity was found to be superior to that of istradefylline, all the while avoiding significant induction of dyskinesia [ 45 ]. In the same model, KW-6356 exhibited the ability to augment the anti-Parkinsonian effects of different doses of L-DOPA [ 46 ].…”

Section: Ars In Cns Diseasesmentioning

confidence: 99%

Pharmacology of Adenosine Receptors: Recent Advancements

Vincenzi,

Pasquini,

Contri

et al. 2023

Biomolecules

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Adenosine receptors (ARs) are widely acknowledged pharmacological targets yet are still underutilized in clinical practice. Their ubiquitous distribution in almost all cells and tissues of the body makes them, on the one hand, excellent candidates for numerous diseases, and on the other hand, intrinsically challenging to exploit selectively and in a site-specific manner. This review endeavors to comprehensively depict the substantial advancements witnessed in recent years concerning the development of drugs that modulate ARs. Through preclinical and clinical research, it has become evident that the modulation of ARs holds promise for the treatment of numerous diseases, including central nervous system disorders, cardiovascular and metabolic conditions, inflammatory and autoimmune diseases, and cancer. The latest studies discussed herein shed light on novel mechanisms through which ARs exert control over pathophysiological states. They also introduce new ligands and innovative strategies for receptor activation, presenting compelling evidence of efficacy along with the implicated signaling pathways. Collectively, these emerging insights underscore a promising trajectory toward harnessing the therapeutic potential of these multifaceted targets.

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“…Adenosine A 2A receptors have been implicated in a variety of central nervous system diseases, including Parkinson's disease (PD), cognitive impairment, Huntington's disease, epilepsy, and attention deficit hyperactivity disorder 2,3 . In nonhuman primate models of PD, oral administration of KW‐6356 has antiparkinsonian effects both as a monotherapy and in combination with levodopa 4,5 . Furthermore, its main plasma metabolite, M6 (the chemical structure presented in Figure S1), has antagonist/inverse agonist activity for the adenosine A 2A receptor that is as potent as that of KW‐6356.…”

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confidence: 99%

Population Pharmacokinetics of the Novel Adenosine A_2A Antagonist/Inverse Agonist KW‐6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson's Disease

Tayama,

Okada,

Ogawa

et al. 2024

Clinical Pharm in Drug Dev

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KW‐6356 is a selective antagonist and inverse agonist of the adenosine A2A receptor. The primary aim of the present analysis was to characterize the pharmacokinetics (PK) of KW‐6356 and its active metabolite M6 in healthy subjects and patients with Parkinson's disease (PD). We pooled concentration‐time data from healthy subjects and patients with PD who were administered KW‐6356. Using these data, we developed a population PK model by sequentially fitting the KW‐6356 parameters followed by the M6 parameters. A first‐order absorption with a 1‐compartment model for KW‐6356 and a 1‐compartment model for M6 best described the profiles. The covariates included in the final models were food status (fed/fasted/unknown) on first‐order absorption rate constant, baseline serum albumin level on apparent clearance of KW‐6356, and baseline body weight on apparent volume of distribution of KW‐6356 and apparent clearance of M6. No covariate had a clinically meaningful impact on KW‐6356 or M6 exposure.

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Anti-parkinsonian activity of the adenosine A2A receptor antagonist/inverse agonist KW-6356 as monotherapy in MPTP-treated common marmosets

Cited by 5 publications

References 47 publications

How can caffeine alleviate the motor symptoms of Parkinson’s disease? – the implications of adenosine 2A receptor antagonism

How can caffeine alleviate the motor symptoms of Parkinson’s disease? – the implications of adenosine 2A receptor antagonism

Pharmacology of Adenosine Receptors: Recent Advancements

Population Pharmacokinetics of the Novel Adenosine A_2A Antagonist/Inverse Agonist KW‐6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson's Disease

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Anti-parkinsonian activity of the adenosine A2A receptor antagonist/inverse agonist KW-6356 as monotherapy in MPTP-treated common marmosets

Cited by 5 publications

References 47 publications

How can caffeine alleviate the motor symptoms of Parkinson’s disease? – the implications of adenosine 2A receptor antagonism

How can caffeine alleviate the motor symptoms of Parkinson’s disease? – the implications of adenosine 2A receptor antagonism

Pharmacology of Adenosine Receptors: Recent Advancements

Population Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW‐6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson's Disease

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Product

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Population Pharmacokinetics of the Novel Adenosine A_2A Antagonist/Inverse Agonist KW‐6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson's Disease