Synthesis and preliminary evaluation of new 1- and 3-[1-(2-hydroxy-3-phenoxypropyl)]xanthines from 2-amino-2-oxazolines as potential A1 and A2A adenosine receptor antagonists.
The development of potent and selective adenosine receptor ligands as potential drugs is an active area of research. Xanthines are one of the most important classes of adenosine receptor antagonists and have been widely developed in terms of affinity and selectivity for adenosine receptors. We recently developed new original pathways for the synthesis of xanthine analogues starting from 5-substituted-2-amino-2-oxazoline 5 as a synthon. These procedures allowed us to selectively introduce a large, functionalized and beta-adrenergic 2-hydroxy-3-phenoxypropyl pharmacophore at the 1- and 3-position of the xanthine moiety which allowed further structural modifications. In this study, we present a new synthetic access to racemic xanthine derivatives 1-4 from 5, and their evaluation as adenosine A1, A2A and A3 receptor ligands in radioligand binding studies. The 2-hydroxy-3-phenoxypropyl moiety was well tolerated in the 3-position of the xanthine core, while its introduction in the 1-position of the xanthine moiety led to a large decrease in adenosine receptor affinity. 1,7-Dimethyl-3-[1-(2-chloro-3-phenoxypropyl)]-8-(3,4,5-trimethoxystyryl)xanthine (2n) was the most potent and selective A2A antagonist of the present series (Ki=44 nM, >>200-fold selective vs A1). 1-Propyl-3-[1-(2-hydroxy-3-phenoxypropyl)]-8-noradamantylxanthine (3f) was identified as a potent (KiA1=21 nM) and highly selective (>>350-fold vs A2A and A3 receptor) adenosine A1 receptor antagonist.
Massip
Stéphane
S
EA 2962-Pharmacochimie, UFR des Sciences Pharmaceutiques, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France.
Guillon
Jean
J
Bertarelli
Daniela
D
Bosc
Jean-Jacques
JJ
Léger
Jean-Michel
JM
Lacher
Svenja
S
Bontemps
Cécile
C
Dupont
Thibaut
T
Müller
Christa E
CE
Jarry
Christian
C
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D014970:Xanthines / Q000138:chemical synthesis* / Q000494:pharmacology*
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D010080:Oxazoles; D014970:Xanthines