N-6,C8-DISUBSTITUTED ADENOSINE DERIVATIVES AS PARTIAL AGONISTS FOR ADENOSINE A(1) RECEPTORS

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.