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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Increased activity of antagonists of growth hormone-releasing hormone substituted at positions 8, 9, and 10
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Increased activity of antagonists of growth hormone-releasing hormone substituted at positions 8, 9, and 10

机译：在位置8、9和10处取代的生长激素释放激素拮抗剂的活性增强

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摘要

Antagonists of human growth hormone-releasing hormone (hGHRH) with increased potency and improved enzymatic and chemical stability are needed for potential clinical applications. We synthesized 21 antagonistic analogs of hGHRH(1-29)NH_2, substituted at positions 8, 9, and 10 of the common core sequence {phenylacetyl-Tyr~1, D-Arg~(2,28), para-chloro-phenylalanine 6, Arg~9/homoarginine 9, Tyr~(10)/O-methyl-tyrosine 10, α-aminobutyric acid 15, norleucine 27, Har~(29)} hGHRH(1-29)NH_2. Inhibitory effects on hGHRH-induced GH release were evaluated in vitro in a superfused rat pituitary system, as well as in vivo after i.v. injection into rats. The binding affinities of the peptides to pituitary GHRH receptors were also determined. Introduction of para-amidinophenylalanine 10 yielded antagonists JV-1-62 and -63 with the highest activities in vitro and lowest receptor dissociation constants (K_i = 0.057-0.062 nM). Antagonists JV-1-62 and -63 also exhibited the strongest effect in vivo, significantly (P < 0.05-0.001) inhibiting hGHRH-induced GH release for at least 1 h. Para-amino-phenylalanine 10 and O-ethyltyrosine 10 substitutions yielded antagonists potent in vitro, but His~(10), 3,3′-diphenylalanine 10, 2-naphthy-lalanine 10, and cyclohexylalanine 10 modifications were detrimental. Antagonists containing citrulline 9 (in MZ-J-7-72), amidinophenylala-nine 9 (in JV-1-65), His~9, D-Arg~9, citrulline 8, Ala~8, D-Ala~8, or α-aminobutyric acid 8 substituents also had high activity and receptor affinity in vitro. However, in vitro potencies of analogs with substitution in position 9 correlated poorly with acute endocrine effects in vivo, as exemplified by the weak and/or short inhibitory actions of antagonists JV-1-65 and MZ-J-7-72 on GH release in vivo. Nevertheless, antagonist JV-1-65 was more potent than JV-1-63 in tests on inhibition of the growth of human prostatic and lung cancer lines xenografted into nude mice. This indicates that oncological activity may be based on several mechanisms. hGHRH antagonists with improved efficacy could be useful for treatment of cancers that depend on insulin-like growth factors or GHRH.
机译：潜在的临床应用需要具有增强的效力以及改善的酶和化学稳定性的人类生长激素释放激素（hGHRH）拮抗剂。我们合成了21种hGHRH（1-29）NH_2的拮抗类似物，它们被替换在共同核心序列{苯乙酰基-Tyr〜1，D-Arg〜（2,28），对氯-苯丙氨酸6，Arg-9 /高精氨酸9，Tyr_（10）/ O-甲基酪氨酸10，α-氨基丁酸15，正亮氨酸27，Har〜（29）} hGHRH（1-29）NH_2。在体外在超融合大鼠垂体系统中以及在静脉内注射后体内评价了对hGHRH诱导的GH释放的抑制作用。注入大鼠。还确定了肽与垂体GHRH受体的结合亲和力。引入对-基苯丙氨酸10产生的拮抗剂JV-1-62和-63具有最高的体外活性和最低的受体解离常数（K_i = 0.057-0.062 nM）。拮抗剂JV-1-62和-63在体内也表现出最强的作用，显着（P <0.05-0.001）抑制hGHRH诱导的GH释放至少1 h。对氨基苯丙氨酸10和O-乙基酪氨酸10替代产生有效的体外拮抗剂，但His〜（10），3,3'-二苯丙氨酸10、2-萘丙氨酸10和环己基丙氨酸10修饰是有害的。包含瓜氨酸9（在MZ-J-7-72中），a基苯丙氨酸9（在JV-1-65中），His〜9，D-Arg〜9，瓜氨酸8，Ala〜8，D-Ala〜8的拮抗剂或α-氨基丁酸8个取代基在体外也具有高活性和受体亲和力。但是，在第9位被取代的类似物的体外效力与体内急性内分泌作用相关性很弱，例如拮抗剂JV-1-65和MZ-J-7-72对GH释放的弱和/或短抑制作用就是例证体内。然而，在抑制异种移植到裸鼠中的人前列腺和肺癌细胞系生长的试验中，拮抗剂JV-1-65比JV-1-63更有效。这表明肿瘤活性可能基于多种机制。疗效更高的hGHRH拮抗剂可用于治疗依赖胰岛素​​样生长因子或GHRH的癌症。

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