Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A<sub>2A</sub> Receptor Antagonists and Their Biological Evaluation

Basu, Sujay; Barawkar, Dinesh A.; Thorat, Sachin; Shejul, Yogesh D.; Patel, Meena; Naykodi, Minakshi; Jain, Vaibhav; Salve, Yogesh; Prasad, V. R.; Chaudhary, Sumit; Ghosh, Indraneel; Bhat, Ganesh; Quraishi, Azfar; Patil, Harish; Ansari, Shariq; Menon, Suraj; Unadkat, Vishal; Thakare, Rhishikesh; Seervi, Madhav; Meru, Ashwinkumar V.; De, Siddhartha; Bhamidipati, Ravi Kanth; Rouduri, Sreekanth R.; Palle, Venkata P.; Chug, Anita; Mookhtiar, Kasim A.

doi:10.1021/acs.jmedchem.6b01584

Cited by 22 publications

(27 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Various computational methods were used to study neuroprotective effect from adenosine A 2A antagonists such as pharmacophore model [68], QSAR, molecular docking [69][70][71], and molecular dynamics [72,73]. Orally bioavailable adenosine A 2A receptor antagonists have been studied for its QSAR and pharmacokinetics properties [74].…”

Section: Current Sources Of the Adenosine A 2a Antagonistmentioning

confidence: 99%

The Role and Development of the Antagonist of Adenosine A_2Ain Parkinson’s Disease

Aryati¹,

Salamah²,

Syahdi³

et al. 2019

Neuroprotection

View full text Add to dashboard Cite

Adenosine is a neuromodulator that regulates the body's response to dopamine and another neurotransmitter in the brain that is responsible for motoric, emotion, learning, and memory function. Adenosine is a G-protein-coupled receptor and has four subtypes, which are A 1, A 2A , A 2B , and A 3. Adenosine A 2A is located in the striatum of the brain. Antagonist interferes with GABA releasing, modulates acetylcholine and releases dopamine, and also facilitates dopamine receptor's signaling. Therefore, it can reduce motoric symptoms in Parkinson's disease. Adenosine A 2A antagonist is also believed to have neuroprotective effects. Several compounds have been reported and have undergone clinical test as selective adenosine A 2A antagonists, including istradefylline, preladenant, tozadenant, vipadenant, ST-1535, and SYN-115. Nonselective adenosine A 2A antagonists from natural compounds are caffeine and theophylline.

show abstract

Section: Current Sources Of the Adenosine A 2a Antagonistmentioning

confidence: 99%

The Role and Development of the Antagonist of Adenosine A_2Ain Parkinson’s Disease

Aryati¹,

Salamah²,

Syahdi³

et al. 2019

Neuroprotection

View full text Add to dashboard Cite

show abstract

“…[86,87] Due to demonstrated treatment options (PD and cancer immunotherapy), novel A 2A AdR antagonists with improved physicochemical, pharmacokinetic and pharmacological properties are being progressively developed. [88] Additionally, new highly selective A 2B AdR antagonists are progressively being identified and some promising drug candidates are under evaluation in clinical trials for the treatment of diabetes, asthma and chronic obstructive pulmonary disease. [89] Selected example of metabolic activation and genotoxicity…”

Section: Recent Pharmaceutical Developments Of a 2a Adr Antagonists Amentioning

confidence: 99%

Safety issues of compounds acting on adenosinergic signalling

Schmidt

Ferk

2017

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

Objectives Much research has been performed on the field of identifying the roles of adenosine and adenosinergic signalling, but a relatively low number of marketing authorizations have been granted for adenosine receptor (AdR) ligands. In part, this could be related to their safety issues; therefore, our aim was to examine the toxicological and adverse effects data of different compounds acting on adenosinergic signalling, including different AdR ligands and compounds resembling the structure of adenosine. We also wanted to present recent pharmaceutical developments of experimental compounds that showed promising results in clinical trial setting. Key findings Safety issues of compounds modulating adenosinergic signalling were investigated, and different mechanisms were presented. Structurally different classes of compounds act on AdRs, the most important being adenosine, adenosine derivatives and other non-nucleoside compounds. Many of them are either not selective enough or are targeting other targets of adenosinergic signalling such as metabolizing enzymes that regulate adenosine levels. Many other targets are also involved that are not part of adenosinergic signalling system such as GABA receptors, different channels, enzymes and others. Some synthetic AdR ligands even showed to be genotoxic. Summary Current review presents safety data of adenosine, adenosine derivatives and other non-nucleoside compounds that modulate adenosinergic signalling. We have presented different mechanisms that participate to an adverse effect or toxic outcome. A separate section also deals with possible organ-specific toxic effects on different in-vitro and in-vivo models.

show abstract

“…Several morpholinobenzo [d]thiazol derivatives of tozadenant containing fluorine in aliphatic (1-3) and aromatic (4-6) positions were recently developed (Figure 2) [18][19][20][21][22]. However, we did not focus on A 2A R ligands containing trifluoromethyl groups due to major limitations of the available labeling methods implicating low radiochemical yields and molar activities [23].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of a Novel 18F-Labeled Radiotracer for PET Imaging of the Adenosine A2A Receptor

Lai

Toussaint

Teodoro

et al. 2021

IJMS

View full text Add to dashboard Cite

The adenosine A2A receptor (A2AR) has emerged as a potential non-dopaminergic target for the treatment of Parkinson’s disease and, thus, the non-invasive imaging with positron emission tomography (PET) is of utmost importance to monitor the receptor expression and occupancy during an A2AR-tailored therapy. Aiming at the development of a PET radiotracer, we herein report the design of a series of novel fluorinated analogs (TOZ1-TOZ7) based on the structure of the A2AR antagonist tozadenant, and the preclinical evaluation of [18F]TOZ1. Autoradiography proved A2AR-specific in vitro binding of [18F]TOZ1 to striatum of mouse and pig brain. Investigations of the metabolic stability in mice revealed parent fractions of more than 76% and 92% of total activity in plasma and brain samples, respectively. Dynamic PET/magnetic resonance imaging (MRI) studies in mice revealed a brain uptake but no A2AR-specific in vivo binding.

show abstract

Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A_2A Receptor Antagonists and Their Biological Evaluation

Cited by 22 publications

References 36 publications

The Role and Development of the Antagonist of Adenosine A_2Ain Parkinson’s Disease

The Role and Development of the Antagonist of Adenosine A_2Ain Parkinson’s Disease

Safety issues of compounds acting on adenosinergic signalling

Synthesis and Biological Evaluation of a Novel 18F-Labeled Radiotracer for PET Imaging of the Adenosine A2A Receptor

Contact Info

Product

Resources

About

Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A2A Receptor Antagonists and Their Biological Evaluation

Cited by 22 publications

References 36 publications

The Role and Development of the Antagonist of Adenosine A2Ain Parkinson’s Disease

The Role and Development of the Antagonist of Adenosine A2Ain Parkinson’s Disease

Safety issues of compounds acting on adenosinergic signalling

Synthesis and Biological Evaluation of a Novel 18F-Labeled Radiotracer for PET Imaging of the Adenosine A2A Receptor

Contact Info

Product

Resources

About

Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A_2A Receptor Antagonists and Their Biological Evaluation

The Role and Development of the Antagonist of Adenosine A_2Ain Parkinson’s Disease

The Role and Development of the Antagonist of Adenosine A_2Ain Parkinson’s Disease