title: A series of ligands displaying a remarkable agonistic-antagonistic profile at the adenosine A1 receptor.
abstract: Adenosine receptor agonists are usually variations of the natural ligand, adenosine. The ribose moiety in the ligand has previously been shown to be of great importance for the agonistic effects of the compound. In this paper, we present a series of nonadenosine ligands selective for the adenosine A(1) receptor with an extraordinary pharmacological profile. 2-Amino-4-benzo[1,3]dioxol-5-yl-6-(2-hydroxyethylsulfanyl)pyridine-3,5-dicarbonitrile (70, LUF 5853) shows full agonistic behavior comparable with the reference compound CPA, while also displaying comparable receptor binding affinity (K(i) = 11 nM). In contrast, compound 58 (2-amino-4-(3-trifluoromethylphenyl)-6-(2-hydroxyethylsulfanyl)pyridine-3,5-dicarbonitrile, LUF 5948) has a binding affinity of 14 nM and acts as an inverse agonist. Also present within this same series are compounds that show neutral antagonism of the adenosine A(1) receptor, for example compound 65 (2-amino-4-(4-difluoromethoxyphenyl)-6-(2-hydroxyethylsulfanyl)pyridine-3,5-dicarbonitrile, LUF 5826).
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, P.O. Box 9502, 2300 RA Leiden, The Netherlands. ijzerman@ladr.leidenuniv.nl
authors.forename: Lisa C W
authors.initials: LC
authors.lastname: Chang
authors.forename: Jacobien K
authors.initials: JK
authors.lastname: von Frijtag Drabbe Künzel
authors.forename: Thea
authors.initials: T
authors.lastname: Mulder-Krieger
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Spanjersberg
authors.forename: Sophie F
authors.initials: SF
authors.lastname: Roerink
authors.forename: Gijs
authors.initials: G
authors.lastname: van den Hout
authors.forename: Margot W
authors.initials: MW
authors.lastname: Beukers
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
mesh_terms: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D004149:Dioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D011869:Radioligand Assay; D013329:Structure-Activity Relationship
chemical_list: C500072:2-amino-4-(3-trifluoromethylphenyl)-6-(2-hydroxyethylsulfanyl)pyridine-3,5-dicarbonitrile; C500071:2-amino-4-benzo(1,3)dioxol-5-yl-6-(2-hydroxyethylsulfanyl)pyridine-3,5-dicarbonitrile; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000631:Aminopyridines; D004149:Dioxoles; D008024:Ligands; D000242:Cyclic AMP