Adenosine A(1) and A(3) selective N-alkoxypurines as novel cytokine modulators and neuroprotectants

The synthesis, purinergic receptor binding, and biological activity of a se ries of navel N-alkoxyadenosine A(3) ligands is described. Several referenc e adenosine A(3) receptor agonists;, e.g,, N-(3-iodobenzyl)adenosine-5'-met hyluronamide (IB-MECA) contain a 4'-ribosylalkylamide moiety as well as a l arge 6-amino substituent. We found that this 4'-amide could be replaced wit h a range of other furanosyl-4'-functional groups including vinyl, chlorome thyl, acetoxymethyl, methoxymethyl, and isoxazolyl; the target molecules ex hibited potent and selective binding to the recombinant human A(3) receptor . Furthermore, the bulky phenylmethyl 6-amino substituent in IB-MECA has be en replaced by methoxy, also with retention of A(3) receptor affinity. The new N-alkoxyadenosine derivatives were examined for their ability to inhibi t the production of the cytokine tumor necrosis factor alpha (TNF-alpha), w hich is indicative of A(3) agonist effect, and some examples exhibited a pr otective effect in both a rodent seizure model and global cerebral ischemia in Mongolian gerbils. Drug Dev. Res. 45:214-221, 1998. (C) 1998 Wiley-Liss , Inc.