Synthesis and characterization of novel 2-amino-3-benzoylthiophene derivatives as biased allosteric agonists and modulators of the adenosine A(1) receptor.
A series of novel 2-amino-3-benzoylthiophenes (2A3BTs) were screened using a functional assay of A(1)R mediated phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in intact CHO cells to identify potential agonistic effects as well as the ability to allosterically modulate the activity of the orthosteric agonist, R-PIA. Two derivatives, 8h and 8i, differing only in terms of the absence or presence of an electron-withdrawing group on the benzoyl moiety of the 2A3BT scaffold, were identified as biased allosteric agonists and positive allosteric modulators of agonist function at the adenosine A(1) receptor (A(1)R) in two different functional assays. Our findings indicate that subtle structural variations can promote functionally distinct receptor conformational states.
Drug Discovery Biology, Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville VIC 3052, Australia.
Celine
C
Valant
Luigi
L
Aurelio
Shane M
SM
Devine
Trent D
TD
Ashton
Jonathan M
JM
White
Patrick M
PM
Sexton
Arthur
A
Christopoulos
Peter J
PJ
Scammells
D058907:Adenosine A1 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C573297:(2-amino-5-methyl-4-(3-(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone; C573296:(2-amino-5-methyl-4-(3-(trifluoromethyl)phenyl)thiophen-3-yl)(phenyl)methanone; D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; D013876:Thiophenes; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3