title: A series of 2,4-disubstituted quinolines as a new class of allosteric enhancers of the adenosine A3 receptor.
abstract: The adenosine receptor subfamily consists of the adenosine A(1), A(2A), A(2B), and A(3) receptors, which are localized in a variety of tissues throughout the human body. It is, therefore, a challenge to develop receptor specific ligands with improved tissue selectivity. Allosteric modulators could have these therapeutic advantages over orthosteric ligands. In the present study, a series of 2,4-disubstituted quinolines were synthesized on the basis of the structure of LUF6000 (34). Compound 27 (LUF6096) was able to allosterically enhance agonist binding to a similar extent as 34. In addition, this new compound showed low, if any, orthosteric affinity for any of the adenosine receptors. In a functional assay, compound 27 showed improved activity in comparison to 34, as it increased both the intrinsic efficacy and the potency of the reference agonist Cl-IB-MECA at the human adenosine A(3) receptor.
authors.affiliation: Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.forename: Anikó
authors.initials: A
authors.lastname: Göblyös
authors.forename: Annelien M
authors.initials: AM
authors.lastname: Zweemer
authors.forename: Renée
authors.initials: R
authors.lastname: Bakker
authors.forename: Thea
authors.initials: T
authors.lastname: Mulder-Krieger
authors.forename: Jacobus P D
authors.initials: JP
authors.lastname: van Veldhoven
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
mesh_terms: D058909:Adenosine A3 Receptor Agonists; D000494:Allosteric Regulation; D000634:Aminoquinolines / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D008024:Ligands; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D058909:Adenosine A3 Receptor Agonists; D000634:Aminoquinolines; D007093:Imidazoles; D008024:Ligands; C511637:N-(3,4-dichlorophenyl)-2-cyclohexyl-1H-imidazo(4,5-c)quinolin-4-amine; D011804:Quinolines