Borrmann Thomas, Abdelrahman Aliaa, Volpini Rosaria, Lambertucci Catia, Alksnis Edgars, Gorzalka Simone, Knospe Melanie, Schiedel Anke C, Cristalli Gloria, Müller Christa E
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
J Med Chem. 2009 Oct 8;52(19):5974-89. doi: 10.1021/jm9006356.
Adenine derivatives bearing substituents in the 2-, N(6)-, 7-, 8-, and/or 9-position and a series of deazapurines were synthesized and investigated in [(3)H]adenine binding studies at the adenine receptor in rat brain cortical membrane preparations (rAde1R). Steep structure-activity relationships were observed. Substitution in the 8-position (amino, dimethylamino, piperidinyl, piperazinyl) or in the 9-position (2-morpholinoethyl) with basic residues or introduction of polar substituents at the 6-amino function (hydroxy, amino, acetyl) represented the best modifications. Functional evaluation of selected adenine derivatives in adenylate cyclase assays at 1321N1 astrocytoma cells stably expressing the rAde1R showed that all compounds investigated were agonists or partial agonists. A subset of compounds was additionally investigated in binding studies at human embryonic kidney (HEK293) cells, which also express a high-affinity adenine binding site. Structure-affinity relationships at the human cell line were similar to those at the rAde1R, but not identical. In particular, N(6)-acetyladenine (25, K(i) rat: 2.85 microM; K(i) human: 0.515 microM) and 8-aminoadenine (33, K(i) rat: 6.51 microM; K(i) human: 0.0341 microM) were much more potent at the human as compared to the rat binding site. The new AdeR ligands may serve as lead structures and contribute to the elucidation of the functions of the adenine receptor family.
合成了在2-、N(6)-、7-、8-和/或9-位带有取代基的腺嘌呤衍生物以及一系列脱氮嘌呤，并在大鼠脑皮质膜制剂（rAde1R）中的腺嘌呤受体的[³H]腺嘌呤结合研究中进行了考察。观察到了陡峭的构效关系。在8-位（氨基、二甲氨基、哌啶基、哌嗪基）或9-位（2-吗啉代乙基）用碱性残基取代，或在6-氨基官能团处引入极性取代基（羟基、氨基、乙酰基）是最佳修饰。在稳定表达rAde1R的1321N1星形细胞瘤细胞的腺苷酸环化酶测定中，对选定的腺嘌呤衍生物进行功能评估，结果表明所有研究的化合物均为激动剂或部分激动剂。还在人胚胎肾（HEK293）细胞的结合研究中对一部分化合物进行了考察，该细胞也表达高亲和力的腺嘌呤结合位点。人细胞系的构效关系与rAde1R相似，但不完全相同。特别是，N(6)-乙酰腺嘌呤（25，大鼠的K(i)：2.85微摩尔；人的K(i)：0.515微摩尔）和8-氨基腺嘌呤（33，大鼠的K(i)：6.51微摩尔；人的K(i)：0.0341微摩尔）与人结合位点相比，对人而言效力要强得多。这些新的AdeR配体可作为先导结构，有助于阐明腺嘌呤受体家族的功能。
