Adenosine A1 and A3 selectiveN-alkoxypurines as novel cytokine modulators and neuroprotectants

Abstract

The synthesis, purinergic receptor binding, and biological activity of a series of novel N-alkoxyadenosine A 3 ligands is described. Several reference adenosine A 3 receptor agonists, e.g., N-(3-iodobenzyl)adenosine-5'-methyluronamide (IB-MECA) contain a 4'-ribosylalkylamide moiety as well as a large 6-amino substituent. We found that this 4'-amide could be replaced with a range of other furanosyl-4'-functional groups including vinyl, chloromethyl, acetoxymethyl, methoxymethyl, and isoxazolyl; the target molecules exhibited potent and selective binding to the recombinant human A 3 receptor. Furthermore, the bulky phenylmethyl 6-amino substituent in IB-MECA has been replaced by methoxy, also with retention of A 3 receptor affinity. The new N-alkoxyadenosine derivatives were examined for their ability to inhibit the production of the cytokine tumor necrosis factor alpha (TNF-α), which is indicative of A 3 agonist effect, and some examples exhibited a protective effect in both a rodent seizure model and global cerebral ischemia in Mongolian gerbils.