N6,9-disubstituted adenines: potent, selective antagonists at the A1 adenosine receptor.
N6,9-disubstituted adenines: potent, selective antagonists at the A1 adenosine receptor.
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N6,9-二取代腺嘌呤：A1 腺苷受体的有效、选择性拮抗剂。
DOI：
10.1021/jm00113a029
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发表时间：
1991
影响因子：
7.3
通讯作者：
Olsson,RA
中科院分区：
文献类型：
--
作者：
Thompson,RD;Secunda,S;Daly,JW;Olsson,RA
Ne-Substituted 9-methyladenines are potent antagonists of the activation of adenosine receptors. The present study assessed the effect of N6 and N-9 substituents on the binding of adenines to the and A2 receptors, respectively, of rat braincortex and striatum and also on the antagonism of the A2 receptor mediated stimulation of the adenylate cyclase of PC12 cells by lV-ethyladenosine-5'-uronamide. The potency ranking of 9-substituted adenines varied directly with the hydrophobicity of the substituent: cyclopentyl> phenyl> tetrahydrofuryl> ethyl> methyl> 2-hydroxyethyl. The 9-substituted adeninesshowed little selectivity for either receptor and the R enantiomer of N®-(l-phenyl-2-propyl)-9-methyladenine was only 4-fold more potent than the S enantiomer at the receptor. An A^-cyclopentyl substituent increased potency at the receptor and decreased potency at the A2 receptor, resulting in selectivity for the receptor of up to 39-fold. The A^-cyclopentyl group completely overshadowed the effect of the hydrophobicityof the 9-substituent. A 2-chloro substituent did not alter the potency of an N6-substituted9-methyladenine.Exocyclic substituents at N6 and C-2 profoundly influ-ence the activitiesof adenosine derivatives at and A2 adenosine receptors (AxAR, A2AR). Thus, certain alkyl and cycloalkyl substituents at N6 can increase the affinity of adenosine for the AxAR, 1-3 whereas some aralkyl sub-stituents at N6 or at C-2 can promote affinity for the A^ R. 4-9 A2-chloro substituent further increases the potency and selectivity of the selectiveAXAR agonist JV®-cyclopentyladenosine. 10 A ribose moiety at N-9 is present in most adenosine receptor agonists. Modification of the ribose usually reduces or even abolishes activity at either receptor. 11, 13 The potent adenosine-5'-ribofuranuronamides and certain other ribosides modified at C-5'are exceptions to this rule. The combination of an N6 substituent that confers selectivityfor the AxAR, together with a 2', 3'-dideoxyribose residue at N-9, generates a po-
