An Open-label, Randomized, Three-arm Study Evaluating the Potential of BMS-984923 to Alter the Systemic Exposure of Three Orally Administered Probe Substrates in Healthy Adult Participants

The goal of this study is to learn if the investigational drug, BMS-984923 will impact the exposure and clearance of other medications when given together. Most drugs are broken down and cleared in the body via cytochrome P450 enzymes in the liver. The metabolism and clearance of certain drugs can be affected by other drugs when dosed together. To evaluate the impact of BMS-984923 on the clearance of other medications, we will investigate three known pathways which may be impacted by BMS-984923.
In this study participants will take one dose of the three known medications, midazolam, caffeine and dextromethorphan together. These drugs are known to be cleared by different cytochrome P450 enzymes. Blood will be collected to evaluate the exposure and clearance of these medications and their primary metabolites. Study participants will then be administered BMS-984923 for 18-days. On the 18th Day of BMS-984923 dosing, participants will again be co-administering midazolam, caffeine and dextromethorphan. Blood will be collected again, and the concentration of each drug will be measured. We will learn in this study if BMS-984923 changes the exposure and metabolism of the known drugs. These results will inform how BMS-984923 can be administered to patients who take multiple medications.

Start Date01 Nov 2024

Sponsor / Collaborator

Allyx Therapeutics, Inc.Startup

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100 Clinical Results associated with A1R x A2aR

100 Translational Medicine associated with A1R x A2aR

0 Patents (Medical) associated with A1R x A2aR

318

Literatures (Medical) associated with A1R x A2aR

01 Jul 2025·Neural regeneration research

Prolonged intermittent theta burst stimulation restores the balance between A2AR- and A1R-mediated adenosine signaling in the 6-hydroxidopamine model of Parkinson's disease.

Article

Author: Ninkovic, Milica ; Jovanovic, Milica Zeljkovic ; Stevanovic, Ivana ; Nedeljkovic, Nadezda ; Stanojevic, Jelena ; Dragic, Milorad ; Ilic, Tihomir V

JOURNAL/nrgr/04.03/01300535-202507000-00027/figure1/v/2024-09-09T124005Z/r/image-tiff An imbalance in adenosine-mediated signaling, particularly the increased A2AR-mediated signaling, plays a role in the pathogenesis of Parkinson's disease. Existing therapeutic approaches fail to alter disease progression, demonstrating the need for novel approaches in PD. Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease. However, the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown. The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling. Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test. Immunoblot, quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen. Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals. A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen. Treatment with intermittent theta burst stimulation began 7 days after the lesion, coinciding with the onset of motor symptoms. After treatment with prolonged intermittent theta burst stimulation, complete motor recovery was observed. This improvement was accompanied by downregulation of the eN/CD73-A2AR pathway and a return to physiological levels of A1R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation. Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A1R and elevated the expression of A2AR. Intermittent theta burst stimulation reversed these effects by restoring the abundances of A1R and A2AR to control levels. The shift in ARs expression likely restored the balance between dopamine-adenosine signaling, ultimately leading to the recovery of motor control.

01 Aug 2024·Biomedicine & Pharmacotherapy

Adenosine and adenosine receptors in metabolic imbalance-related neurological issues

Review

Author: Song, Juhyun ; Jang, Mi-Hyeon

Metabolic syndromes (e.g., obesity) are characterized by insulin resistance, chronic inflammation, impaired glucose metabolism, and dyslipidemia. Recently, patients with metabolic syndromes have experienced not only metabolic problems but also neuropathological issues, including cognitive impairment. Several studies have reported blood-brain barrier (BBB) disruption and insulin resistance in the brain of patients with obesity and diabetes. Adenosine, a purine nucleoside, is known to regulate various cellular responses (e.g., the neuroinflammatory response) by binding with adenosine receptors in the central nervous system (CNS). Adenosine has four known receptors: A1R, A2AR, A2BR, and A3R. These receptors play distinct roles in various physiological and pathological processes in the brain, including endothelial cell homeostasis, insulin sensitivity, microglial activation, lipid metabolism, immune cell infiltration, and synaptic plasticity. Here, we review the recent findings on the role of adenosine receptor-mediated signaling in neuropathological issues related to metabolic imbalance. We highlight the importance of adenosine signaling in the development of therapeutic solutions for neuropathological issues in patients with metabolic syndromes.

01 Jun 2024·Brain Research

Adora2A downregulation promotes caffeine neuroprotective effect against LPS-induced neuroinflammation in the hippocampus

Article

Author: Bernardes Carvalho, Liebert ; Latini, Alexandra ; Birbrair, Alexander ; Rodrigues Ferreira, Marcel ; Martha Bernardi, Maria ; Lemes Dos Santos Sanna, Paula ; de Carvalho, Kassia ; Aires, Rogério ; Cristina Dos Santos Afonso, Camila ; Foganholi da Silva, Rodrigo A ; Souza, Jennyffer

Caffeine has been extensively studied in the context of CNS pathologies as many researchers have shown that consuming it reduces pro-inflammatory biomarkers, potentially delaying the progression of neurodegenerative pathologies. Several lines of evidence suggest that adenosine receptors, especially A₁ and A₂A receptors, are the main targets of its neuroprotective action. We found that caffeine pretreatment 15 min before LPS administration reduced the expression of Il1b in the hippocampus and striatum. The harmful modulation of caffeine-induced inflammatory response involved the downregulation of the expression of A₂A receptors, especially in the hippocampus. Caffeine treatment alone promoted the downregulation of the adenosinergic receptor Adora2A; however, this promotion effect was reversed by LPS. Although administering caffeine increased the expression of the enzymes DNA methyltransferases 1 and 3A and decreased the expression of the demethylase enzyme Tet1, this effect was reversed by LPS in the hippocampus of mice that were administered Caffeine + LPS, relative to the basal condition; no significant differences were observed in the methylation status of the promoter regions of adenosine receptors. Finally, the bioinformatics analysis of the expanded network demonstrated the following results: the Adora2B gene connects the extended networks of the adenosine receptors Adora1 and Adora2A; the Mapk3 and Esr1 genes connect the extended Adora1 network; the Mapk4 and Arrb2 genes connect the extended Adora2A network with the extended network of the proinflammatory cytokine Il1β. These results indicated that the anti-inflammatory effects of acute caffeine administration in the hippocampus may be mediated by a complex network of interdependencies between the Adora2B and Adora2A genes.

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