title: 2-Amino-6-furan-2-yl-4-substituted nicotinonitriles as A2A adenosine receptor antagonists.
abstract: A 2A adenosine receptor antagonists usually have bi- or tricyclic N aromatic systems with varying substitution patterns to achieve desired receptor affinity and selectivity. Using a pharmacophore model designed by overlap of nonxanthine type of previously known A 2A antagonists, we synthesized a new class of compounds having a 2-amino nicotinonitrile core moiety. From our data, we conclude that the presence of at least one furan group rather than phenyl is beneficial for high affinity on the A 2A adenosine receptor. Compounds 39 (LUF6050) and 44 (LUF6080) of the series had K i values of 1.4 and 1.0 nM, respectively, with reasonable selectivity toward the other adenosine receptor subtypes, A 1, A 2B, and A 3. The high affinity of 44 was corroborated in a cAMP second messenger assay, yielding subnanomolar potency for this compound.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, DiVision of Medicinal Chemistry, PO Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Monica
authors.initials: M
authors.lastname: Mantri
authors.forename: Olivier
authors.initials: O
authors.lastname: de Graaf
authors.forename: Jacobus
authors.initials: J
authors.lastname: van Veldhoven
authors.forename: Anikó
authors.initials: A
authors.lastname: Göblyös
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: Regina
authors.initials: R
authors.lastname: Link
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
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: D058917:Adenosine A2 Receptor Antagonists; D000588:Amines / Q000737:chemistry*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D005663:Furans / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009539:Nicotinic Acids / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D009570:Nitriles / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000588:Amines; D005663:Furans; D009539:Nicotinic Acids; D009570:Nitriles; D043705:Receptor, Adenosine A2A; D000242:Cyclic AMP; C039281:furan