7-Deaza-2-phenyladenines: structure-activity relationships of potent A1 selective adenosine receptor antagonists

Abstract

A series of derivatives of 7-deazapurines with varying substituents in the 2-, 6-, and 9-position was synthesized in an attempt to improve the adenosine receptor affinity and A1 or A2 selectivity. The adenosine receptor affinities were assessed by measuring the inhibition of [3H]-(R)-N6-(phenylisopropyl) adenosine (R-PIA) binding to rat brain A1 and inhibition of [3H]-5'-(N-ethylcarboxamido)adenosine (NECA) binding to rat striatum A2 adenosine receptors. A selected set of compounds representing the main structural variations was further examined in adenosine receptor coupled adenylate cyclase assays. All tested compounds antagonized the inhibition of adenylate cyclase elicited by interaction of R-PIA with A1 receptors in rat fat cell membranes and the activation of adenylate cyclase elicited by interaction of NECA with A2 receptors of pheochromocytoma PC12 cell membranes. The results indicate that 7-deazahypoxanthines have a potential for A2 selectivity, while all 7-deazaadenines are A1 selective. Introduction of a phenyl residue in the 2-position of 7-deazaadenines increases A1 activity tremendously. 2-(p-Chlorophenyl)-7,8-dimethyl-9-phenyl-7-deazaadenine (29) is potent and specific for the A1 receptors of rat brain (Ki = 122 nM), having no affinity for the A2 receptors of rat striatum. The compound has low activity at the A2 receptors of rat PC12 cell membranes where it appears to act as a noncompetitive inhibitor. A 1-phenylethyl substituent at the 9-position was found to be superior to a phenyl residue in terms of A1 affinity. The most potent A1 antagonist in the present series is the highly A1 selective (790-fold) (R)-7,8-dimethyl-2-phenyl-9-(1-phenylethyl)-7-deazaadenine (31, Ki = 4.7 nM), which is 30-35 times more potent at A1 receptors than its S enantiomer. The solubility of six of the potent 7-deaza-2-phenyladenines was determined by means of an A1 binding assay. Chloro substitution of the 2-phenyl ring appeared to improve the solubility as well as the solubility over A1 affinity ratio of 9-phenyl- and 9-(1-phenylethyl)-substituted 7-deazadenines.

Non‐Xanthine Antagonists for the Adenosine A1 Receptor

“…Sect. 4.1.2) [79]. The fusion of a six-membered ring at C(7) and C(8) of the deazapurine gives rise to this series.…”

“…The most significant finding of this paper was the importance of the Ph group at C(7) of the ring. Further investigations of the 7-phenylpyrrolo[2,3-d]pyrimidin-4-amines revealed that a Ph group at C(2) was also beneficial (i.e., 29) [79]. Modifying the 7-Ph group to a chiral moiety showed that the (R)-enantiomer 30 was much preferred to the (S)-enantiomer 31 [79].…”

“…This compound had very little selectivity over the A 2A receptor [79]. Later work showed the 4-NH 2 group (i.e., 107) to be favourable, with the inclusion of an aromatic substituent at C(2) and a chiral moiety at N(9) [80].…”

“…Further investigations of the 7-phenylpyrrolo[2,3-d]pyrimidin-4-amines revealed that a Ph group at C(2) was also beneficial (i.e., 29) [79]. Modifying the 7-Ph group to a chiral moiety showed that the (R)-enantiomer 30 was much preferred to the (S)-enantiomer 31 [79]. Incorporating these features also improved the selectivity for A 1 receptors over the A 2(A) receptors dramatically.…”

“…Changing the position of the chiral 1-phenylethyl group from C(7) of the ring to attachment to the exocyclic amine did not change the affinity for the A 1 receptor significantly, but did improve selectivity dramatically (i.e., 32). Campbell et al [81] synthesized a library set of pyrrolo [2,3-d]pyrimidines, which included the most significant features as described previously by M¸ller et al [79], varying only at the exocyclic N-atom. The findings here were tested at the human adenosine receptors and showed compounds in the nm range, although with a loss in selectivity (i.e., 33).…”