H. Roelen et al., N-6,C8-DISUBSTITUTED ADENOSINE DERIVATIVES AS PARTIAL AGONISTS FOR ADENOSINE A(1) RECEPTORS, Journal of medicinal chemistry, 39(7), 1996, pp. 1463-1471
The synthesis and biological evaluation of N-6,C8-disubstituted deriva
tives of adenosine as potential partial agonists for adenosine recepto
rs is described. Via three routes, two series of compounds were prepar
ed, viz., N-6-cyclopentyladenosine derivatives 3a-e and C8-(cyclopenty
lamino)adenosine analogs 3e and 9a-d, respectively. The X-ray structur
e determination of one of these compounds, N-6-ethyl-8-(cyclopentylami
no)adenosine (9b), was carried out (orthorhombic, space group P2(1)2(1
)2(1) (No. 19) with a = 11.039(3), b = 8.708(2), and c = 24.815(12) An
gstrom, Z = 4, R1 = 0.0974, R2(w) = 0.2455). Due to intramolecular hyd
rogen bonding, the ribose moiety df this compound is in an anti confor
mation. The compounds were tested in vitro in radioligand binding stud
ies, yielding their affinities for Al and Az, adenosine receptors. All
compounds appeared AL selective, with affinities in the high nanomola
r, low micromolar range. On A(1) receptors the so-called GTP shift was
also determined, i.e., the ratio between the affinities measured in t
he 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 N-6-cyclope
ntyladenosine derivatives showed lower intrinsic activities than the p
rototypic full agonist N-6-cyclopentyladenosine on the decrease in hea
rt rate in conscious, normotensive rats.