Suppr超能文献

发现一类新型的人神经激肽-3受体选择性非肽拮抗剂。1. 4-喹啉甲酰胺骨架的鉴定。

Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 1. Identification of the 4-quinolinecarboxamide framework.

作者信息

Giardina G A, Sarau H M, Farina C, Medhurst A D, Grugni M, Raveglia L F, Schmidt D B, Rigolio R, Luttmann M, Vecchietti V, Hay D W

机构信息

Department of Chemistry, SmithKline Beecham S.p.A. Milano, Italy.

出版信息

J Med Chem. 1997 Jun 6;40(12):1794-807. doi: 10.1021/jm960818o.

Abstract

A novel class of potent and selective non-peptide neurokinin-3 (NK-3) receptor antagonists, featuring the 4-quinolinecarboxamide framework, has been designed based upon chemically diverse NK-1 receptor antagonists. The novel compounds 33-76, prompted by chemical modifications of the prototype 4, have been characterized by binding analysis using a membrane preparation of chinese hamster ovary (CHO) cells expressing the human neurokinin-3 receptors (hNK-3-CHO), and clear structure-activity relationships (SARs) have been established. From SARs, (R)-N-[alpha-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide (65, SB 218795, hNK-3-CHO binding Ki = 13 nM) emerged as one of the most potent compounds of this novel class. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that 65 is about 90-fold selective for hNK-3 versus hNK-2 receptors (hNK-2-CHO binding Ki = 1221 nM) and over 7000-fold selective versus hNK-1 receptors (hNK-1-CHO binding Ki = > 100 microM). In vitro functional studies in rabbit isolated iris sphincter muscle preparation demonstrated that 65 is a competitive antagonist of the contractile response induced by the potent and selective NK-3 receptor agonist senktide with a Kb = 43 nM. Overall, the data indicate that 65 is a potent and selective hNK-3 receptor antagonist and a useful lead for further chemical optimization.

摘要

基于多种化学结构不同的神经激肽-1(NK-1)受体拮抗剂,设计出了一类新型的强效且选择性的非肽类神经激肽-3(NK-3)受体拮抗剂,其具有4-喹啉甲酰胺骨架。新型化合物33 - 76是对原型化合物4进行化学修饰后得到的,通过使用表达人神经激肽-3受体(hNK-3-CHO)的中国仓鼠卵巢(CHO)细胞膜制剂进行结合分析对其进行了表征,并建立了明确的构效关系(SARs)。从构效关系研究中,(R)-N-[α-(甲氧基羰基)苄基]-2-苯基喹啉-4-甲酰胺(65,SB 218795,hNK-3-CHO结合Ki = 13 nM)成为这类新型化合物中活性最强的化合物之一。与其他神经激肽受体(hNK-2-CHO和hNK-1-CHO)的选择性研究表明,65对hNK-3受体的选择性比对hNK-2受体高约90倍(hNK-2-CHO结合Ki = 1221 nM),对hNK-1受体的选择性超过7000倍(hNK-1-CHO结合Ki = > 100 μM)。在兔离体虹膜括约肌制备物中的体外功能研究表明,65是强效且选择性的NK-3受体激动剂senktide诱导的收缩反应的竞争性拮抗剂,Kb = 43 nM。总体而言,数据表明65是一种强效且选择性的hNK-3受体拮抗剂,是进一步化学优化的有用先导化合物。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验