N6-substituted N-alkyladenosine-5'-uronamides: bifunctional ligands having recognition groups for A1 and A2 adenosine receptors.
N6-substituted N-alkyladenosine-5'-uronamides: bifunctional ligands having recognition groups for A1 and A2 adenosine receptors.
复制标题
N6-取代的N-烷基腺苷-5-糖醛酰胺：具有A1和A2腺苷受体识别基团的双功能配体。
DOI：
10.1021/jm00159a020
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发表时间：
1986
影响因子：
7.3
通讯作者：
Daly,JW
中科院分区：
文献类型：
--
作者：
Olsson,RA;Kusachi,S;Thompson,RD;Ukena,D;Padgett,W;Daly,JW
The coronary vasoactivity of iV-ethyl-l'-deoxy-l'-(6-amino-9. ff-purin-9-yl)-dD-ribofuranuronamide (ÑECA, 1) is over 2 orders of magnitudegreater than that of adenosine, and the vasoactivity of certain N6-substitutedadenosines 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 l-deoxy-l-(6-chloro-9H-purin-9-yl)-2', 3'-0-isopropylidene-dD-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, lV-alkyl (or aryll-A^-alklarlyl-adenosine-S'-uronamides. At the coronary artery A2 receptor the potency of Ne-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 plasmamembranes 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 Al receptor of rat brain thepotency 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 IV-ethyl-A^-S-pentyladenosine-S'-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 Al or A2 adenosine receptors, adenosine analogues interact with both the N6 andthe 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.Adenosine receptors that either inhibit (Al or Ri) or stimulate (A2 or Ra) the activity of adenylate cyclase mediate many of the biological effects of adenosine. Frequently these receptors are identified pharmacologically by the rank order of potency within sets of adenosine analogues that include N6-substituted adenosines and AT-alkyladenosine-S'-uronamides. At Al receptors the N6-substituted adenosines are very potent, whereas at A2 receptors the adenosine-5'-uronamides are likewise very potent. 1, 2 Thus, selectivity for one or the other receptor depends on the chemical attributes of, literally, the op-posite ends of the adenosine molecule. iV-Ethyl-l'-deoxy-1'-(6-amino-9/f-purin-9-yl)-/5-D-ribofuranuronamide (ÑECA, 1), the prototypic A2 adenosine receptor agonist, is an exceedingly potent coronary vaso-dilator. Structure-activity correlations show that 1 and
