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Design, Synthesis, and Pharmacological Characterization of 2-(2-Furanyl)thiazolo[5,4-d]pyrimidine-5,7-diamine Derivatives: New Highly Potent A 2A Adenosine Receptor Inverse Agonists with Antinociceptive Activity.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2016 Dec 08; Vol. 59 (23), pp. 10564-10576. Date of Electronic Publication: 2016 Nov 29. - Publication Year :
- 2016
-
Abstract
- In this study, we describe the design and synthesis of new N <superscript>5</superscript> -substituted-2-(2-furanyl) thiazolo[5,4-d]pyrimidine-5,7-diamines (2-18) and their pharmacological characterization as A <subscript>2A</subscript> adenosine receptor (AR) antagonists by using in vitro and in vivo assays. In competition binding experiments two derivatives (13 and 14) emerged as outstanding ligands showing two different affinity values (KH and KL) for the hA <subscript>2A</subscript> receptor with the high affinity KH value in the femtomolar range. The in vitro functional activity assays, performed by using cyclic AMP experiments, assessed that they behave as potent inverse agonists at the hA <subscript>2A</subscript> AR. Compounds 13 and 14 were evaluated for their antinociceptive activity in acute experimental models of pain showing an effect equal to or greater than that of morphine. Overall, these novel inverse agonists might represent potential drug candidates for an alternative approach to the management of pain.
- Subjects :
- Acetic Acid
Adenosine A2 Receptor Agonists chemical synthesis
Adenosine A2 Receptor Agonists chemistry
Analgesics chemical synthesis
Analgesics chemistry
Animals
CHO Cells
Cricetulus
Cyclic AMP antagonists & inhibitors
Cyclic AMP metabolism
Diamines chemical synthesis
Diamines chemistry
Dose-Response Relationship, Drug
Female
Humans
Mice
Molecular Structure
Pain chemically induced
Pyrimidines chemical synthesis
Pyrimidines chemistry
Structure-Activity Relationship
Thiazoles chemical synthesis
Thiazoles chemistry
Adenosine A2 Receptor Agonists pharmacology
Analgesics pharmacology
Diamines pharmacology
Drug Design
Pain drug therapy
Pyrimidines pharmacology
Receptor, Adenosine A2A metabolism
Thiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 59
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 27933962
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.6b01068