Synthesis and structure-activity relationships of 3,7-dimethyl-1-propargylxanthine derivatives, A2A-selective adenosine receptor antagonists

Journal of Medicinal Chemistry
C E MüllerJesús Sandoval-Ramírez

Abstract

A series of 8-substituted derivatives of 3,7-dimethyl-1-propargylxanthine (DMPX) was synthesized and investigated as A2A adenosine receptor antagonists. Different synthetic strategies for the preparation of DMPX derivatives and analogues were explored. A recently developed synthetic procedure starting from 3-propargyl-5,6-diaminouracil proved to be the method of choice for the preparation of this type of xanthine derivatives. The novel compounds were investigated in radioligand binding studies at the high-affinity adenosine receptor subtypes A1 and A2A and compared with standard A2A adenosine receptor antagonists. Structure-activity relationships were analyzed in detail. 8-Styryl-substituted DMPX derivatives were identified that exhibit high affinity and selectivity for A2A adenosine receptors, including 8-(m-chlorostyryl)-DMPX (CS-DMPX, Ki A2A = 13 nM, 100-fold selective), 8-(m-bromostyryl)-DMPX (BS-DMPX, Ki A2A = 8 nM, 146-fold selective), and 8-(3,4-dimethoxystyryl)-DMPX (Ki A2A = 15 nM, 167-fold selective). These and other novel compounds are superior to the standard A2A adenosine receptor antagonists KF17837 (4) and CSC (5) with respect to A2A affinity and/or selectivity.

Citations

May 17, 2003·European Journal of Medicinal Chemistry·Pier Giovanni BaraldiPier Andrea Borea
Dec 27, 2008·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Jacobus P PetzerCornelis J Van der Schyf
Jun 28, 2000·Journal of the Autonomic Nervous System·J W Daly
Feb 8, 2005·Psychopharmacology·Marcello SolinasSteven R Goldberg
Jun 6, 2000·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·C E MüllerR Sauer
Dec 13, 2012·Expert Opinion on Drug Discovery·Werner J Geldenhuys, Cornelis J Van der Schyf
Jun 9, 2000·Kidney International·G GabriëlsM Steinhausen
Oct 26, 2005·Il Farmaco·Barkin BerkKenneth A Jacobson
Mar 12, 2003·Bioorganic & Medicinal Chemistry·Jacobus P PetzerNeal Castagnoli
May 3, 2006·Bioorganic & Medicinal Chemistry Letters·Dipak PrajapatiAshim J Thakur
Aug 30, 2005·Bioorganic & Medicinal Chemistry·Anu AgarwalSuman Gupta
Jun 24, 2014·Journal of Medicinal Chemistry·Nikolay T TzvetkovChrista E Müller
Dec 21, 2006·ChemMedChem·Gloria CristalliRosaria Volpini
Dec 29, 2005·Medicinal Research Reviews·Stefano MoroGiampiero Spalluto
Aug 29, 2000·Phytotherapy Research : PTR·J B CalixtoR A Yunes
Dec 28, 2010·Biochimica Et Biophysica Acta·Christa E Müller, Kenneth A Jacobson
Jan 10, 2008·Chemical Reviews·Pier Giovanni BaraldiPier Andrea Borea

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.