Varnavas A, Lassiani L, Valenta V
Department of Pharmaceutical Sciences, University of Trieste, Italy.
Farmaco. 2000 May;55(5):369-75. doi: 10.1016/s0014-827x(00)00053-7.
We have described previously an innovative bond disconnection strategy of asperlicin, a naturally occurring CCK receptor antagonist, leading to anthranilic acid dimer and tryptophan synthons. We have also demonstrated that when the tryptophan residue is connected to the C- or N-terminal sides of the anthranilic acid dimer, compounds with similar micromolar CCK-A receptor affinities are obtained. In order to investigate the binding effects of different N-terminal substitution, in this paper we describe a new series of anthranilic acid dimer derivatives, characterized by the presence of the tryptophan residue in the C-terminus of the dimer. Among the compounds synthesized, the N-1H-indol-3-propionyl derivative exhibited an improved, at the micromolar range, affinity for the CCK-A receptor in comparison to that of either, the N-unsubstituted derivative and asperlicin. The lead compound emerging from this key step of our investigation represents the new starting point for the development of a new class of CCK-A receptor ligands.
我们之前已经描述过一种创新的天冬酰胺素（一种天然存在的胆囊收缩素受体拮抗剂）的键断裂策略，该策略可生成邻氨基苯甲酸二聚体和色氨酸合成子。我们还证明，当色氨酸残基连接到邻氨基苯甲酸二聚体的C端或N端时，可得到具有相似微摩尔级胆囊收缩素A受体亲和力的化合物。为了研究不同N端取代的结合效应，本文我们描述了一系列新的邻氨基苯甲酸二聚体衍生物，其特征是二聚体的C端存在色氨酸残基。在合成的化合物中，与N未取代的衍生物和天冬酰胺素相比，N-1H-吲哚-3-丙酰基衍生物在微摩尔范围内对胆囊收缩素A受体表现出更高的亲和力。我们研究这一关键步骤中出现的先导化合物代表了开发一类新型胆囊收缩素A受体配体的新起点。
