American Chemical Society
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N6,C8-Disubstituted Adenosine Derivatives as Partial Agonists for Adenosine A1 Receptors

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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. IJzerman
The 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 3ae and C8-(cyclopentylamino)adenosine analogs 3e and 9ad, 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.