促黄体生成激素释放激素小型拮抗剂的体外和体内活性

In vitro and in vivo activities of reduced-size antagonists of luteinizing hormone-releasing hormone.

作者信息

Haviv F, Fitzpatrick T D, Nichols C J, Bush E N, Diaz G, Bammert G, Nguyen A T, Johnson E S, Knittle J, Greer J

机构信息

TAP Pharmaceuticals, Inc., Abbott Park, Illinois.

出版信息

J Med Chem. 1994 Mar 4;37(5):701-5. doi: 10.1021/jm00031a021.

DOI:10.1021/jm00031a021

PMID:7510341

Abstract

A novel series of octapeptide LHRH antagonists was designed on the basis of the structure of the (2-9) fragment of a LHRH agonist. By adopting a systematic SAR study, we were able to improve first the in vitro activity and then the in vivo LH suppression, raising them up to the range of the decapeptide antagonists NalGlu (51) and A-75998 (50), resulting in A-76154 (49). The octapeptide antagonist A-76154 is the most potent reduced-size LHRH antagonist reported. It suppresses LH in the castrated rat by over 80% for a period of 4 h following sc bolus administration of 30 micrograms/kg.

摘要

基于促黄体激素释放激素（LHRH）激动剂（2-9）片段的结构设计了一系列新型八肽LHRH拮抗剂。通过系统的构效关系（SAR）研究，我们首先提高了体外活性，然后提高了体内促黄体生成素（LH）抑制作用，使其达到十肽拮抗剂NalGlu（51）和A-75998（50）的范围，从而得到A-76154（49）。八肽拮抗剂A-76154是报道中活性最强的缩短型LHRH拮抗剂。在去势大鼠中，皮下大剂量注射30微克/千克后4小时内，它能抑制LH超过80%。