Dual Anta-Inhibitors Targeting Protein Kinase CK1δ and A Adenosine Receptor Useful in Neurodegenerative Disorders.

Currently, the number of patients with neurodegenerative pathologies is estimated at over one million, with consequences also on the economic level. Several factors contribute to their development, including overexpression of A adenosine receptors (AAR) in microglial cells and up-regulation and post-translational alterations of some casein kinases (CK), among them, CK-1δ. The aim of the work was to study the activity of AAR and CK1δ in neurodegeneration using in-house synthesized A/CK1δ dual anta-inhibitors and to evaluate their intestinal absorption.

"Dual Anta-Inhibitors" of the A Adenosine Receptor and Casein Kinase CK1delta: Synthesis, Biological Evaluation, and Molecular Modeling Studies.

Based on a screening of a chemical library of A adenosine receptor (AR) antagonists, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of the enzyme casein kinase 1 delta (CK1δ) and to bind adenosine receptors (ARs). Some derivatives, here called "dual anta-inhibitors", demonstrated good CK1δ inhibitory activity combined with a high binding affinity, especially for the AAR. The -methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (, IC = 0.

A patent review of adenosine A receptor antagonists (2016-present).

Introduction: A adenosine receptor (AAR) plays a crucial role in pathophysiologic conditions associated with high adenosine release, typical of airway inflammatory pathologies, gastrointestinal disorders, cancer, asthma, type 2 diabetes, and atherosclerosis. In some pathologies, simultaneous inactivation of A and AARs is desirable to have a synergism of action that leads to a greater efficacy of the pharmacological treatment and less side effects due to the dose of drug administered. In this context, it is strongly required to identify molecules capable of selectively antagonizing AAR or A/AARs.

A Adenosine Receptor Antagonists with Nucleoside Structures and Their Anticancer Activity.

The overexpression of the A adenosine receptor (AR) in a number of cancer cell types makes it an attractive target for tumor diagnosis and therapy. Hence, in the search for new AAR ligands, a series of novel 2,-disubstituted adenosines (Ados) was synthesized and tested in radioligand binding and functional assays at ARs. Derivatives bearing a 2-phenethylamino group in the -position were found to exert higher AAR affinity and selectivity than the corresponding -(2,2-diphenylethyl) analogues.

A Adenosine Receptor Antagonists and their Potential in Neurological Disorders.

Endogenous nucleoside adenosine modulates a number of physiological effects through interaction with P1 purinergic receptors. All of them are G protein-coupled receptors, and, to date, four subtypes have been characterized and named A, A, A, and A. In recent years, adenosine receptors, particularly the A subtype, have become attractive targets for the treatment of several neurodegenerative disorders, known to involve neuroinflammation, like Parkinson's and Alzheimer's diseases, multiple sclerosis, and neuropsychiatric conditions.