title: 3- and 6-Substituted 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridines as A1 adenosine receptor allosteric modulators and antagonists.
abstract: A series of 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridines were prepared and evaluated as potential allosteric modulators at the A(1) adenosine receptor. The structure-activity relationships of the 3- and 6-positions of a series of 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridines were explored. Despite finding that 3- and 6-substituted 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridines possess the ability to recognize an allosteric site on the agonist-occupied A(1)AR at relatively high concentrations, the structural modifications we have performed on this scaffold favor the expression of orthosteric antagonist properties over allosteric properties. This research has identified 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridines as novel class of orthosteric antagonist of the A(1)AR and highlighted the close relationship between structural elements governing allosteric modulation and orthosteric antagonism of agonist function at the A(1)AR.
authors.affiliation: Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville VIC 3052, Australia.
authors.forename: Luigi
authors.initials: L
authors.lastname: Aurelio
authors.forename: Celine
authors.initials: C
authors.lastname: Valant
authors.forename: Heidi
authors.initials: H
authors.lastname: Figler
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Flynn
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D000494:Allosteric Regulation; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D009682:Magnetic Resonance Spectroscopy; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000187:drug effects* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D011725:Pyridines; D043682:Receptor, Adenosine A1