Coumarins and adenosine receptors: New perceptions in structure–affinity relationships. (4th September 2017)

• Record Type: Journal Article
• Authors: Fonseca, André; Matos, Maria João; Vilar, Santiago; Kachler, Sonja; Klotz, Karl‐Norbert; Uriarte, Eugenio; Borges, Fernanda
• Is Part Of: Chemical biology & drug design. Volume 91:Number 1(2018)
• Page Start: 245
• Page End: 256
• Publication Date: 2017-09-04
• Subjects: adenosine receptors -- carboxamidocoumarin -- coumarins; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13075
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : Adenosine receptor (AR) subtypes are involved in several physiological and pharmacological processes. Ligands that are able to selectively modulate one receptor subtype can delay or slow down the progression of diverse diseases. In this context, our research group focused its investigation into the discovery and development of novel, potent and selective AR ligands based on coumarin scaffold. Therefore, a series of 3‐phenylcarboxamidocoumarins were synthesized and their affinity for the human AR subtypes was screened by radioligand binding assays for A1, A2A and A3 receptors and for A2B by adenylyl cyclase assay. Compound26 was found to be the most remarkable, with a h A1 / h A3 and h A2A / h A3 selectivity of 42, for the A3 AR ( K i = 2.4 μm ). Receptor‐driven molecular modelling studies have provided valuable information on the binding/selectivity data of compound26 and for the following optimization process. Moreover, compound26 presents drug‐like properties according to the general guidelines linked to the concept. Abstract : A series of 3‐phenylcarboxamidocoumarins were synthesized and their affinity for the human AR subtypes was screened for A1, A2A and A3 and A2B receptors Compound26 was found to be the most remarkable, with a h A1 / h A3 and h A2A / h A3 selectivity of 42, for the A3 AR ( K i = 2.4 μm ). Receptor‐driven molecular modelling studies have provided valuable information on the binding/selectivity data of compound26 and for the following optimization process.