N6-substituted N-alkyladenosine-5'-uronamides: bifunctional ligands having recognition groups for A1 and A2 adenosine receptors.
The coronary vasoactivity of N-ethyl-1'-deoxy-1'-(6-amino-9H-purin-9-yl)-beta-D-ribofuranuronamide (NECA, 1) is over 2 orders of magnitude greater than that of adenosine, and the vasoactivity of certain N6-substituted adenosines is as much as 1 order of magnitude greater. Such results suggest that a combination of appropriate modifications at N6 and C-5' might additively augment the agonist potency of adenosine. At low temperatures 1-deoxy-1-(6-chloro-9H-purin-9-yl)-2',3'-O-isopropylidene- beta-D-ribofuranosyl chloride (5), obtained in three steps from inosine, reacts with amines to yield uronamides. The subsequent reaction of such uronamides with amines at elevated temperatures displaces the purine 6-chloro group to yield, after deblocking, N-alkyl(or aryl)-N6-alk(ar)yl-adenosine-5'-uronamides. At the coronary artery A2 receptor the potency of N6-modified analogues of 1 is similar to that of the N6-substituted adenosine, rather than equal to or greater than 1. As agonists in the A2 receptor-mediated stimulation of adenylate cyclase in plasma membranes of PC12 pheochromocytoma cells or human platelets, N6-substituted analogues of 1 are intermediate between the high potency of 1 and the lower potency of the N6-substituted adenosines. At the A1 receptor of rat brain the potency of an N6-substituted analogue of 1 is often greater than that of the corresponding N6-substituted adenosine. At all four receptors, replacing the ethyl group of N-ethyl-N6-3-pentyladenosine-5'-uronamide by larger alkyl groups reduces potency; amides of secondary amines are inactive or have only marginal activity. Analogues of 1 containing a chiral center in the N6 substituent retain the stereoselectivity characteristic of each of the four receptors. Thus, at either A1 or A2 adenosine receptors, adenosine analogues interact with both the N6 and the C-5' receptor regions. However, the effects of N6 and C-5' modifications on potency are less than additive, evidence that the interaction of a substituent with its receptor region influences the interaction of other substituents with their respective receptor regions.
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000310:Adrenal Gland Neoplasms / Q000201:enzymology; D000818:Animals; D001667:Binding, Competitive; D001681:Biological Assay; D001792:Blood Platelets / Q000201:enzymology; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D006801:Humans; D008024:Ligands; D010673:Pheochromocytoma / Q000201:enzymology; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D011983:Receptors, Purinergic; D013329:Structure-Activity Relationship
D008024:Ligands; D011956:Receptors, Cell Surface; D011983:Receptors, Purinergic; D000262:Adenylyl Cyclases; D000241:Adenosine