Synthesis of 2-amino-3-heteroaroylthiophenes and evaluation of their activity as potential allosteric enhancers at the human A1 receptor
Synthesis of 2-amino-3-heteroaroylthiophenes and evaluation of their activity as potential allosteric enhancers at the human A1 receptor
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DOI：
10.1016/j.ejmech.2004.06.009
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发表时间：
2004-10-01
影响因子：
6.7
通讯作者：
Romagnoli, R
中科院分区：
文献类型：
--
作者：
Baraldi, PG;Pavani, MG;Romagnoli, R
2-氨基-3-苯甲酰噻吩是激动剂与腺苷A受体结合的变构增强剂。合成了以杂芳基代替噻吩3位苯甲酰的新化合物。苯基环被具有能形成氢键的杂原子的杂环取代（化合物2-13中的2-呋喃基、2-苯并呋喃基、2-吡啶基）或苯基环的巯基部分作为同位异构体（化合物14-29中的2-噻吩基、3-噻吩基和5-卤-2-巯基）。测定了噻吩环上4位和5位几个烷基取代基对增强剂活性的影响。新分子降低表达人腺苷A受体的CHO细胞中cAMP含量的能力进行了评估。含氢键杂原子的化合物2-13没有表现出明显的变构增强活性。另一方面，化合物15-16和19-20以未取代的噻吩基部分取代苯基环，其效果几乎与原型A变构增强剂PD 81723相同。噻吩环第4和第5位的烷基取代基可耐受，而取代的哌啶环则不能耐受。我们得出结论，在容纳2-氨基-3-苯甲酰噻吩衍生物苯基环的受体结构域中不能形成氢键，表明该结构域是疏水的。(C) 2004 Elsevier SAS。版权所有。
2-Amino-3-benzoylthiophenes are allosteric enhancers of agonist binding to the adenosine A, receptor. New compounds bearing an heteroaroyl instead of the benzoyl moiety at the 3-position of the thiophene were synthesized. The phenyl ring was replaced with heterocycles that possess heteroatoms able to form hydrogen bonds (2-furanyl, 2-benzofuranyl, 2-pyridinyl in compounds 2-13) or with a thienyl moiety as isoster of the phenyl ring (2-thienyl, 3-thienyl and 5-halo-2-thienyl in compounds 14-29). The effect of several alkyl substituents at positions 4 and 5 of the thiophene ring to increase enhancer activity was determined. The ability of the new molecules to reduce the cAMP content in CHO cells expressing the human adenosine A, receptor was evaluated. Compounds 2-13 with hydrogen bond-forming heteroatoms did not show significant activity as allosteric enhancers. On the other hand, compounds 15-16 and 19-20 with an unsubstituted thienyl moiety as replacement for the phenyl ring were nearly as efficacious as PD 81,723, the prototypical A, allosteric enhancer. Alkyl substituents at positions 4 and 5 of the thiophene ring were tolerated while a substituted piperidine ring was not tolerated. We conclude that hydrogen bonds could not be formed in the domain of the receptor that accommodates the phenyl ring of 2-amino-3-benzoylthiophene derivatives, indicating that this domain is hydrophobic. (C) 2004 Elsevier SAS. All rights reserved.