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Download fileN6,C8-Disubstituted Adenosine Derivatives as Partial Agonists for Adenosine A1 Receptors†
journal contribution
posted on 1996-03-29, 00:00 authored by Harlof Roelen, Nora Veldman, Anthony L. Spek, Jacobien von Frijtag Drabbe Künzel, Ron A. A. Mathôt, Ad P. IJzermanThe synthesis and biological evaluation of
N6,C8-disubstituted derivatives of adenosine
as
potential partial agonists for adenosine receptors is described.
Via three routes, two series of
compounds were prepared, viz.,
N6-cyclopentyladenosine derivatives
3a−e and C8-(cyclopentylamino)adenosine analogs 3e and
9a−d, respectively. The X-ray structure
determination of
one of these compounds,
N6-ethyl-8-(cyclopentylamino)adenosine
(9b), was carried out (orthorhombic, space group
P212121 (No. 19) with
a = 11.039(3), b = 8.708(2), and
c = 24.815(12) Å,
Z = 4, R1 = 0.0974,
R2w = 0.2455). Due to intramolecular
hydrogen bonding, the ribose moiety
of this compound is in an anti conformation. The
compounds were tested in vitro in radioligand
binding studies, yielding their affinities for A1 and
A2a adenosine receptors. All compounds
appeared A1 selective, with affinities in the high
nanomolar, low micromolar range. On A1
receptors the so-called GTP shift was also determined, i.e.,
the ratio between the affinities
measured in the presence and absence of 1 mM GTP. All GTP shifts
(values between 1.1 and
3.8) were lower than the GTP shift for CPA (6.0). This GTP shift
appeared indicative for partial
agonism in vivo, since the
N6-cyclopentyladenosine derivatives showed lower
intrinsic activities
than the prototypic full agonist
N6-cyclopentyladenosine on the decrease in heart
rate in
conscious, normotensive rats.