N6-cyclopentyl-3'-substituted-xylofuranosyladenosines: a new class of non-xanthine adenosine A1 receptor antagonists.
The present study explores the C-3' site of the 3-deoxy-3-xylofuranosyl ring of nucleoside analogues with an adenine or N6-cyclopentyladenine (CPA) base moiety and evaluates the effect on adenosine receptor affinity. Two series of sugar-modified adenosines, i.e., 3'-amido-3'-deoxyadenosines and 3'-amidated 3'-deoxyxylofuranosyladenines, were synthesized and tested for their affinity at A1 and A2a receptors in rat brain cortex and rat striatum, respectively. The modest affinity found in the "xylo series" prompted us to synthesize the corresponding N6-cyclopentyl derivatives, which proved to be well accommodated by the A1 receptors with potencies in the lower nanomolar range. This represents a new perspective in the purinergic field. The absence of a GTP-induced shift, i.e., the ratio between the affinities measured in the presence and absence of 1 mM GTP indicates an antagonistic behavior of this new class of CPA analogues.
Van Calenbergh
S
S
Laboratory for Medicinal Chemistry (FFW), University of Ghent, Belgium.
von Frijtag Drabbe Künzel
J K
JK
Blaton
N M
NM
Peeters
O M
OM
Rozenski
J
J
Van Aerschot
A
A
De Bruyn
A
A
De Keukeleire
D
D
IJzerman
A P
AP
Herdewijn
P
P
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D058915:Purinergic P1 Receptor Antagonists; D011869:Radioligand Assay; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology
D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; C048599:N(6)-cyclopentyladenosine; D000241:Adenosine