Nakagawa S H, Yang D C, Flouret G
J Med Chem. 1981 Feb;24(2):221-3. doi: 10.1021/jm00134a021.
As part of our studies on the design of agonists of the luteinizing hormone-releasing hormone (LH-RH), we have synthesized the [des-Gly-NH2(10)]-LH-RH N-methylhydrazide (1), the corresponding thiosemicarbazide (2), and the N-formyl- (3) N-acetyl- (4) and N-(trifluoroacetyl)hydrazide (5). Analogue 1 may be regarded as isosteric with [des-Gly-NH2(10)]-LH-RH N-alkylamides which are, in general, potent agonists. Analogues 2-5 may be regarded as isosteric with [aza-Gly-NH2(10)]-OH-RH, which is equipotent with the hormone. The required protected intermediates were prepared by solid-phase synthesis, and the free peptides were prepared from them by deprotection with HF, followed by purification on Sephadex G-25. Bioassay of these analogues with rat hemipituitaries in vitro showed the following values as percentages of the hormonal values for the release of LH and FSH respectively: N-methylhydrazide (1), 17 and 11%; semithiocarbazide (2), 6.5 and 4.6%; N-formylhydrazide (3), 15.3 and 10%; N-acetylhydrazide (4), 1.2 and 0.6%; N-(trifluoroacetyl)hydrazide (5), 1.0 and 0.9%. Thus, these types of isosteric substitutions are inimical to the preservation of the high biological activity of LH-RH.
作为我们对促黄体生成素释放激素（LH-RH）激动剂设计研究的一部分，我们合成了[去甘氨酰胺（10）]-LH-RH N-甲基酰肼（1）、相应的氨基硫脲（2）以及N-甲酰基-（3）、N-乙酰基-（4）和N-（三氟乙酰基）酰肼（5）。类似物1可被视为与一般具有强效激动剂作用的[去甘氨酰胺（10）]-LH-RH N-烷基酰胺等电子体。类似物2 - 5可被视为与与激素等效的[氮杂甘氨酰胺（10）]-OH-RH等电子体。所需的保护中间体通过固相合成制备，游离肽则通过用HF脱保护从它们制备，随后在葡聚糖G - 25上进行纯化。用大鼠半垂体进行的这些类似物的体外生物测定显示，以下数值分别为LH和FSH释放的激素值的百分比：N-甲基酰肼（1），17%和11%；氨基硫脲（2），6.5%和4.6%；N-甲酰基酰肼（3），15.3%和10%；N-乙酰基酰肼（4），1.2%和0.6%；N-（三氟乙酰基）酰肼（5），1.0%和0.9%。因此，这些类型的等电子取代不利于保留LH-RH的高生物活性。
