Hocart S J, Nekola M V, Coy D H
J Med Chem. 1987 Apr;30(4):739-43. doi: 10.1021/jm00387a030.
The reductive alkylation of the D-Lys side chain in position 6 of the LH-RH antagonist [N-Ac-D-Nal1,D-Phe2,3,D-Arg6,Phe7,D-Ala10]LH-RH was investigated in an attempt to reduce the histamine-releasing activity inherent to most potent antagonists while retaining high antiovulatory activity. The protected parent analogue was prepared by conventional solid-phase peptide synthesis. After selective removal of the Lys Fmoc side-chain protection, the resin-bound peptide was readily and conveniently alkylated at the epsilon amino group with various aldehydes and ketones in the presence of NaCNBH3. The analogues were then cleaved from the resin with simultaneous deprotection by anbydrous hydrogen fluoride and purified to homogeneity in two stages: gel permeation followed by preparative reversed-phase liquid chromatography. The analogues were assayed in standard rat antiovulatory and in vitro histamine-release assays. Simple alkyl groups such as ethyl, isopropyl, neopentyl, and cyclohexyl caused little reduction in histamine-releasing activity while exhibiting antiovulatory activity similar to that of the parent peptide. The presence of benzyl and substituted benzyl groups resulted in substantial losses of both histamine-releasing and antiovulatory activities. Thus, results showed that alterations in the hydrophobicity and size of the position-6 side chain have little effect on histamine-releasing activity or antiovulatory activity as long as a high degree of basicity is retained.
研究了促黄体生成素释放激素（LH-RH）拮抗剂[N-乙酰基-D-萘丙氨酸1，D-苯丙氨酸2,3，D-精氨酸6，苯丙氨酸7，D-丙氨酸10]中第6位D-赖氨酸侧链的还原烷基化反应，旨在降低大多数强效拮抗剂固有的组胺释放活性，同时保留高抗排卵活性。通过传统的固相肽合成法制备了受保护的母体类似物。选择性去除赖氨酸的芴甲氧羰基（Fmoc）侧链保护基后，在树脂上的肽在氰基硼氢化钠存在下，能方便地与各种醛和酮在ε-氨基处进行烷基化反应。然后用无水氟化氢同时进行脱保护，将类似物从树脂上裂解下来，并分两个阶段纯化至均一性：凝胶渗透，然后是制备型反相液相色谱。在标准大鼠抗排卵和体外组胺释放试验中对类似物进行了测定。简单的烷基，如乙基、异丙基、新戊基和环己基，对组胺释放活性的降低作用很小，同时表现出与母体肽相似的抗排卵活性。苄基和取代苄基的存在导致组胺释放活性和抗排卵活性均大幅丧失。因此，结果表明，只要保持高度的碱性，第6位侧链疏水性和大小的改变对组胺释放活性或抗排卵活性影响很小。
