2-aminothienopyridazines as novel adenosine A1 receptor allosteric modulators and antagonists.
2-aminothienopyridazines as novel adenosine A1 receptor allosteric modulators and antagonists.
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DOI：
10.1021/jm800557d
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发表时间：
2008-10-09
影响因子：
7.3
通讯作者：
Scammells PJ
中科院分区：
文献类型：
--
作者：
Ferguson GN;Valant C;Horne J;Figler H;Flynn BL;Linden J;Chalmers DK;Sexton PM;Christopoulos A;Scammells PJ
基于药效团的筛选鉴定了32种化合物，包括5-氨基-3-（4-叔丁基苯基）-4-氧代-3，4-二氢噻吩并[3，4-d]哒嗪-1-羧酸乙酯（8），其为腺苷A1受体（A1 AR）的新变构调节剂。在此基础上，制备了各种衍生物，并评价了对人A1 AR的活性。许多测试化合物在解离动力学测定中变构稳定激动剂-受体-G蛋白三元复合物，但在随后的ERK 1/2磷酸化功能测定中发现作为拮抗剂更有效。对最有效的拮抗剂13 b进行的研究A1 AR介导的[35 S]GTPγS结合和[3 H]CCPA平衡结合的其他实验证实了其拮抗作用模式，并确定了反向激动作用。因此，这项研究确定了一类新的A1 AR拮抗剂，也可以识别受体的变构位点，效力较低。
A pharmacophore-based screen identified 32 compounds including ethyl 5-amino-3-(4-tert-butylphenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylate (8) as a new allosteric modulator of the adenosine A1 receptor (A1AR). On the basis of this lead, various derivatives were prepared and evaluated for activity at the human A1AR. A number of the test compounds allosterically stabilized agonist-receptor-G protein ternary complexes in dissociation kinetic assays, but were found to be more potent as antagonists in subsequent functional assays of ERK1/2 phosphorylation. Additional experiments on the most potent antagonist, 13b, investigating A1AR-mediated [35S]GTPγS binding and [3H]CCPA equilibrium binding confirmed its antagonistic mode of action and also identified inverse agonism. This study has thus identified a new class of A1AR antagonists that can also recognize the receptor’s allosteric site with lower potency.
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影响因子：
6.7
作者：
Baraldi, PG;Pavani, MG;Romagnoli, R
通讯作者：
Romagnoli, R
影响因子：
2.6
作者：
Romagnoli, R;Baraldi, PG;Borea, PAA
通讯作者：
Borea, PAA
影响因子：
2.7
作者：
Baraldi, PG;Zaid, AN;Romagnoli, R
通讯作者：
Romagnoli, R
影响因子：
--
作者：
Osmond, RIW;Sheehan, A;Dyer, AR
通讯作者：
Dyer, AR
影响因子：
3.5
作者：
Nikolakopoulos, G;Figler, H;Scammells, PJ
通讯作者：
Scammells, PJ