Highly selective adenosine A2 receptor agonists in a series of N-alkylated 2-aminoadenosines

Abstract

A wide variety of 2-substituted aminoadenosines were prepared for comparison with the moderately A2 receptor selective adenosine agonist 2-anilinoadenosine (CV-1808). High selectivity combined with significant affinity at the A2 receptor in rat membranes was observed for those amines bearing a two-carbon chain to which was attached an aryl, heteroaryl, or alicyclic moiety. 2-(2-Phenethylamino)adenosine (3d), a 14-fold A2 selective compound, was modified by introduction of a variety of substituents in the benzene ring and the side chain. Some of these changes led to improved A2 affinity and increased selectivity. Replacement of the phenyl moiety by cyclohexenyl produced a 210-fold selective agonist 3ag (CGS 22989) whereas the cyclohexanyl analogue 3af (CGS 22492) was 530-fold selective at the A2 site. These compounds showed hypotensive activity in rat models over a range of doses without the bradycardia observed with less selective agonists.

Adenosine A1 and A2 receptors: Structure–function relationships

“…Studies of the dependence of potency on the size of the ring in N6-cycloalkyl substituted analogs identified CHA and CPA as particularly potent and A,-selective (280-and 780-fold, respecti~ely).~7 Subsequent studies showed that N6-bicycloalkyladenosines are even more A, selective, with the lR, 2S, 4s isomer of N6-(2-endo-norborny1)adenosine(S-ENBA, 4) being 4700-fold selective, while its 5'-C1 analog is even 16,000-fold selective for the A, receptor.48 The N6-region is essentially hydrophobic in nature, and may accommodate very large substituents. Hydrophilic 58 Further structural modifications at the 2-position led to development of 2-alkoxyaden~sines,~~ e.g., CHEA (27; A,: 22nM; A,: 1580 nM),60 2-aralkoxyadenosine derivatives,61 such as MPEA (28; A,: 11 nM; A,: 49 nM),60 as well as 2-alkynyladenosines . 62 For example, the 2-alkynyl derivatives 2-hexynyladenosine (2-HNA, 29) and 2-octynyladenosine (2-ONA, 30) are potent A, agonists (K, values 4 and 12 nM) with 36-and 17-fold selectivity, respectively, for the A, receptor in binding assays.…”

Structure-Activity Relationships for 2-Substituted Adenosines at A₁ and A₂ Adenosine Receptors

“…Be cause the guinea pig was the species for the physiological preparations and the rat the spe cies for the biochemical preparations, a few of the 2-substituted adenosines were compared in heart preparations and in brain binding assays for both guinea pig and rats [41], Spe cies differences were present, but they were not of a magnitude or diversity that negated the present cross-species comparison of activ ities in rat biochemical preparations with ac tivities previously found for guinea pig physi ological preparations. Recently, a series of 2-alkylamino-and 2-aralkylaminoadenosines were reported, many of which were selective for A: receptors [42].…”

Highlights on the Development of A2A Adenosine Receptor Agonists and Antagonists

“…From the whole series, which includes 2-amino-, [80] 2-hydrazino-, [32,45,81] 2-alkoxy-, [82] 2-alkylthio-, [83][84][85] and 2-alkynyl-derivatives, [37,38,77,79] the compounds showing the highest A 2A affinity bore a phenylethyl (or cyclohexylethyl) group directly linked to the heteroatom or triple bond (see Table 1 compounds 4-9).…”