The synthesis, purinergic receptor binding, and biological activity of a series of novel N‐alkoxyadenosine A3 ligands is described. Several reference adenosine A3 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 A3 receptor. Furthermore, the bulky phenylmethyl 6‐amino substituent in IB‐MECA has been replaced by methoxy, also with retention of A3 receptor affinity.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 A3 agonist effect, and some examples exhibited a protective effect in both a rodent seizure model and global cerebral ischemia in Mongolian gerbils. Drug Dev. Res. 45:214–221, 1998. © 1998 Wiley‐Liss, Inc.