Design, Synthesis, and Pharmacological Characterization of 2-(2-Furanyl)thiazolo[5,4-d]pyrimidine-5,7-diamine Derivatives: New Highly Potent A2A Adenosine Receptor Inverse Agonists with Antinociceptive Activity

Flavia Varano; Daniela Catarzi; Fabrizio Vincenzi; Marco Betti; Matteo Falsini; Annalisa Ravani; Pier Andrea Borea; Vittoria Colotta; Katia Varani

doi:10.1021/acs.jmedchem.6b01068

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

J Med Chem. 2016 Dec 8;59(23):10564-10576. doi: 10.1021/acs.jmedchem.6b01068. Epub 2016 Nov 29.

Authors

Flavia Varano¹, Daniela Catarzi¹, Fabrizio Vincenzi², Marco Betti¹, Matteo Falsini¹, Annalisa Ravani², Pier Andrea Borea², Vittoria Colotta¹, Katia Varani²

Affiliations

¹ Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze , via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy.
² Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara , via Fossato di Mortara 17-19, 44121, Ferrara, Italy.

PMID: 27933962
DOI: 10.1021/acs.jmedchem.6b01068

Abstract

In this study, we describe the design and synthesis of new N⁵-substituted-2-(2-furanyl) thiazolo[5,4-d]pyrimidine-5,7-diamines (2-18) and their pharmacological characterization as A_2A 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_2A 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_2A 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetic Acid
Adenosine A2 Receptor Agonists / chemical synthesis
Adenosine A2 Receptor Agonists / chemistry
Adenosine A2 Receptor Agonists / pharmacology*
Analgesics / chemical synthesis
Analgesics / chemistry
Analgesics / pharmacology*
Animals
CHO Cells
Cricetulus
Cyclic AMP / antagonists & inhibitors
Cyclic AMP / metabolism
Diamines / chemical synthesis
Diamines / chemistry
Diamines / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Female
Humans
Mice
Molecular Structure
Pain / chemically induced
Pain / drug therapy*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Receptor, Adenosine A2A / metabolism*
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

2-(2-furanyl)thiazolo(5,4-d)pyrimidine-5,7-diamine
Adenosine A2 Receptor Agonists
Analgesics
Diamines
Pyrimidines
Receptor, Adenosine A2A
Thiazoles
Cyclic AMP
Acetic Acid