Izdebski J, Pinski J, Horvath J E, Halmos G, Groot K, Schally A V
Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70146, USA.
Proc Natl Acad Sci U S A. 1995 May 23;92(11):4872-6. doi: 10.1073/pnas.92.11.4872.
Analogs of the 29 amino acid sequence of human growth hormone-releasing hormone (hGH-RH) with agmatine (Agm) in position 29, desaminotyrosine (Dat) in position 1, norleucine (Nle) in position 27, and L-alpha-aminobutyric acid (Abu) in position 15 have been synthesized, and their biological activity was evaluated. Some peptides contained one or two residues of ornithine (Orn) instead of Lys in positions 12 and 21 and additional replacements in positions 8 and 28. All analogs were found to be more potent than hGH-RH-(1-29)-NH2 in the superfused rat pituitary cell system. In tests in vivo in rats after subcutaneous administration, the analogs JI-22, [Dat1, Orn12,21, Abu15, Nle27, Agm29]hGH-RH-(1-29); JI-34, [Dat1, Orn12,21,Abu15,Nle27, Asp28, Agm29]hGH-RH-(1-29); JI-36, [Dat1, Thr8, Orn12,21, Abu15,Nle27,Asp28,Agm29]hGH-RH-(1-29); and JI-38, [Dat1,Gln8, Orn12,21,Abu15,Nle27,Asp28,Agm29]hGH-RH-(1 -29) displayed a potency 44.6,80.9,95.8, and 71.4 times greater, respectively, than that of hGH-RH-(1-29)-NH2 at 15 min and 217.1, 89.7, 87.9, and 116.8 times greater at 30 min. After intravenous administration, JI-22, JI-36, and JI-38 were 3.2-3.8 times more potent than hGH-RH-(1-29)-NH2 at 5 min and 6.1-8.5 times more active at 15 min. All analogs were found to have higher binding affinities for GH-RH receptors on rat pituitary cells than hGH-RH-(1-29)-NH2. Because of high activity and greater stability, these analogs could be considered for therapy of patients with growth hormone deficiency.
已合成了人生长激素释放激素（hGH-RH）29个氨基酸序列的类似物，其中第29位为胍丁胺（Agm），第1位为去氨基酪氨酸（Dat），第27位为正亮氨酸（Nle），第15位为L-α-氨基丁酸（Abu），并对其生物活性进行了评估。一些肽在第12位和第21位含有一个或两个鸟氨酸（Orn）残基而非赖氨酸，且在第8位和第28位有其他替换。在灌流大鼠垂体细胞系统中，发现所有类似物均比hGH-RH-(1-29)-NH2更具活性。在大鼠皮下给药后的体内试验中，类似物JI-22，即[Dat1, Orn12,21, Abu15, Nle27, Agm29]hGH-RH-(1-29)；JI-34，即[Dat1, Orn12,21,Abu15,Nle27, Asp28, Agm29]hGH-RH-(1-29)；JI-36，即[Dat1, Thr8, Orn12,21, Abu15,Nle27,Asp28,Agm29]hGH-RH-(1-29)；以及JI-38，即[Dat1,Gln8, Orn12,21,Abu15,Nle27,Asp28,Agm29]hGH-RH-(1 -29)，在15分钟时的活性分别比hGH-RH-(1-29)-NH2高44.6、80.9、95.8和71.4倍，在30分钟时分别高217.1、89.7、87.9和116.8倍。静脉给药后，JI-22、JI-36和JI-38在5分钟时的活性比hGH-RH-(1-29)-NH2高3.2 - 3.8倍，在15分钟时高6.1 - 8.5倍。发现所有类似物对大鼠垂体细胞上的GH-RH受体的结合亲和力均高于hGH-RH-(1-29)-NH2。由于这些类似物具有高活性和更高的稳定性，可考虑用于治疗生长激素缺乏症患者。
