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Adenosine A 1 and A 3 selective N ‐alkoxypurines as novel cytokine modulators and neuroprotectants
Author(s) -
Knutsen Lars J.S.,
Sheardown Malcolm J.,
Roberts Stanley M.,
Mogensen John P.,
Olsen Uffe Bang,
Thomsen Christian,
Bowler Andrew N.
Publication year - 1998
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199811/12)45:3/4<214::aid-ddr19>3.0.co;2-k
Subject(s) - adenosine , cytokine , chemistry , pharmacology , medicine , biochemistry
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 Furthermore, the bulky phenylmethyl 6‐amino substituent in IB‐MECA has been replaced by methoxy, also with retention of A 3 receptor affinity.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. Drug Dev. Res. 45:214–221, 1998. © 1998 Wiley‐Liss, Inc.