ChemInform Abstract: Chiral Pyrrolo(2,3‐d)pyrimidine and Pyrimido(4,5‐b)indole Derivatives: Structure‐Activity Relationships of Potent, Highly Stereoselective A1‐ Adenosine Receptor Antagonists.

Abstract

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Structure−Activity Relationships of Adenine and Deazaadenine Derivatives as Ligands for Adenine Receptors, a New Purinergic Receptor Family

“…All compounds investigated showed agonistic effects at rAde1R expressed in astrocytoma cells as shown in Figure 2A. 8-(1-Piperidinyl)adenine (35), 8-aminoadenine (33), and 9-(2-morpholinoethyl)adenine (58) showed about the same efficacy as adenine. 8-Dimethylaminoadenine (42) was even more efficacious than the physiological agonist, showing 137% of the maximal effect of adenine.…”

“…47 The phenylsulfanyl moiety was introduced via direct nucleophilic substitution of 8-bromoadenine (26) with thiophenol in the presence of potassium carbonate, yielding 8-phenylsulfanyladenine (32). 30 8-Aminoadenine (33) was prepared by heating 26 with sodium azide in DMF at 100 °C, followed by hydrogenation of the 8-azido function in the presence of 10% palladium on charcoal. 48 Treatment of 26 with benzylamine, piperidine, pyrrolidine, or piperazine at 150 °C provided the respective 8-aminoadenine derivatives 34-37.…”

“…All adenine derivatives inhibited [ 3 H]adenine uptake at least to a certain degree. N 6 -Acetyladenine (25), N 6 -hydroxyadenine (23), 8-aminoadenine (33), and 9-(2-morpholinoethyl)adenine (58) were most potent, while compounds with a larger 8-substituent (35,37,42) showed lower inhibitory potency (Figure 3). SAR were clearly different from those at the rat adenine receptor.…”

“…Certain adenine derivatives have also been found to induce the production of interferon and to promote the dedifferentiation of committed cells into multipotent progenitor-type cells . Deazaadenine derivatives have been developed as adenosine receptor antagonists. − However, structure−activity relationships (SAR) for adenine derivatives appear to be very different for the AdeR as compared to other targets: the limited data available so far ,, indicate very steep SAR with only few and minor modifications tolerated by the AdeR. The most potent compounds described so far are 2-fluoroadenine ( K i = 0.62 μM), 8-thioadenine ( K i = 2.77 μM), and N 6 -methyladenine ( K i = 3.64 μM), all of which were >20-fold weaker than adenine itself ( K i = 0.0292 μM) in [ 3 H]adenine binding studies performed at rat brain cortical membranes .…”