New 2,6,9-trisubstituted adenines as adenosine receptor antagonists: a preliminary SAR profile

Abstract

A new series of 2,6,9-trisubstituted adenines (5-14) have been prepared and evaluated in radioligand binding studies for their affinity at the human A 1 , A 2A and A 3 adenosine receptors and in adenylyl cyclase experiments for their potency at the human A 2B subtype. From this preliminary study the conclusion can be drawn that introduction of bulky chains at the N 6 position of 9-propyladenine significantly increased binding affinity at the human A 1 and A 3 adenosine receptors, while the presence of a chlorine atom at the 2 position resulted in a not univocal effect, depending on the receptor subtype and/or on the substituent present in the N 6 position. However, in all cases, the presence in the 2 position of a chlorine atom favoured the interaction with the A 2A subtype. These results demonstrated that, although the synthesized compounds were found to be quite inactive at the human A 2B subtype, adenine is a useful template for further development of simplified adenosine receptor antagonists with distinct receptor selectivity profiles.

New substituted 9-propyladenine derivatives as A2Aadenosine receptor antagonists

“…The two isomers were characterized by a comparison of NMR data with analogue purine derivatives. 13,17 In fact, the N-9 alkylated adenines showed an upfield shift of the H-8 and NH 2 protons with respect to the same protons of the N-7 isomers. Furthermore, the N-9 isomers are always obtained in higher yields and show lower polarity in the TLC run such as in compounds 22 with respect to 22a.…”

“…The synthesis of 2-alkylamino-9-propyl derivatives 12-20 was realized by reaction of commercially available 2,6-dichloropurine with propyliodide in the presence of potassium carbonate as previously reported (Scheme 1). 13 After separation of the formed N9 and N7 isomers (10 and 10a, respectively) by chromatography, compound 10 was reacted with ammonia to give the 6-amino derivative 11. 13 Reaction of 11 with the suitable amine at 120 °C for 24 h furnished the 2-phenylalkylamino-9propyl adenines 12-14 with yields ranging from 45 to 88%.…”

“…13 After separation of the formed N9 and N7 isomers (10 and 10a, respectively) by chromatography, compound 10 was reacted with ammonia to give the 6-amino derivative 11. 13 Reaction of 11 with the suitable amine at 120 °C for 24 h furnished the 2-phenylalkylamino-9propyl adenines 12-14 with yields ranging from 45 to 88%. Treatment of 12-14 with N-bromosuccinimide (NBS), in DMF at room temperature, gave the 8-bromoderivatives 15-17 with yields from 35 to 50%.…”

“…10 In many papers, we have demonstrated that the introduction of diverse substituents in the 2, N 6 , 8, and 9-positions of adenine led to AR antagonists endowed with different affinities and selectivities for the four AR subtypes. [11][12][13][14][15][16] In particular, at human receptors, the 9-ethyladenine (1; Fig. 1) resulted in an AR antagonist endowed with μM affinity at the A 1 and A 2A subtypes while it was not able to bind the A 2B and A 3 receptors at concentrations up to 100 μM (1: K i A 1 = 7400 nM, K i A 2A = 2200 nM).…”

A2A Receptor Ligands: Past, Present and Future Trends

“…Furthermore several 2,6,-substituted 9-propyladenines were prepared and tested for their affinity and potency at human AARs. From the SAR of these compounds it resulted that introduction of bulky chains at the N6 position of 9-propyladenine significantly increased binding affinity at the human A 1 AR and A 3 AR, while the presence of a chlorine atom at the 2 position favoured the interaction with A 2A AR [131].…”