Neuropeptides--molecular Mechanism Of Action

由Dmt-Tic药效团组成的强效δ -阿片受体选择性拮抗剂是通过直接改变二肽的c端来修饰的，其中质子化氮是伯胺或叔胺。在Tic和第三芳香族核之间含有或不含间隔（连接）的c端取代基，开发了一系列新的类阿片；尽管c端延长，但它们都表现出高的δ亲和性，在某些情况下，化合物获得了高的mu亲和性，其亲和性增加了几个数量级。6种含bid类似物的生物活性表现为δ拮抗剂/拮抗剂、δ拮抗剂/拮抗剂和δ拮抗剂/拮抗剂混合作用。其中一种化合物具有强效的受体激动作用（IC50 = 9.9），这是首次将受体拮抗剂（pA2 = 9.2）转化为受体激动剂。数据验证了δ亲和不需要带负电荷，芳香性和第三芳香核与Tic之间的距离是非常关键的。所有这些活性的关键残留物是Dmt；虽然Tic被认为是拮抗作用的原因，但它在激动剂中的存在对这一假设提出了质疑。在吡嗪酮环或烷基链周围形成的两个新的含dmt的合成类似物系列正在开发中，这可能为我们提供新的mu激动剂来减轻癌症引起的疼痛和术后疼痛。

Summary of Work: The potent delta-opioid receptor selective anatgonist consisting of the Dmt-Tic pharmacophore was modified by direct changes at the C-terminus of the dipeptide, in which the protonated nitrogen was either a primary or teriary amine. A new series of opioids was developed containing C-terminal substituents with or without a spacer (linker) between Tic and a third aromatic nucleus; in spite of the C-terminal extension, they all exhibited high delta affinities and in some cases the compounds gained high mu affinity, which increased by orders of magnitude. The bioactivity of six Bid-containing analogues indicated mixied delta antagonism/mu agonism, delta agonism/mu agonism and delta antagonism/mu antagonism. One compound had potent delta agonism (IC50 = 9.9), which is the first time a delta antagonist (pA2 = 9.2) was transformed into a delta agonist. The data verified that delta affinity does not require a negative charge, and that aromaticity and the distance between the third aromatic nucleus and that of Tic is highly critical. The key residue for all these activities was Dmt; although Tic was thought to be responsible for antagonism, its presence in an agonist sheds doubt on this hypothesis. Two new series of synthetic Dmt-containing analogues formed around the pyrazinone ring or alkyl chains are being developed that might provide us with new mu agonists to alleviate cancer-induced pain and post-operative pain.