生长激素释放激素（GH-RH）新型胍丁胺类似物的体内[校正后]生物活性评估。

Bokser L, Zarandi M, Schally A V

Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, Louisiana.

Life Sci. 1990;46(14):999-1005. doi: 10.1016/0024-3205(90)90023-k.

The effects of agmatine analogs of growth hormone releasing hormone (GH-RH) were compared to GH-RH(1-29)-NH2 after intravenous (iv) and subcutaneous (sc) administration to pentobarbital-anesthetized male rats. After the iv injection, the analogs [desNH2-Tyr1,Ala15,Nle27] GH-RH(1-28)Agm (MZ-2-51); [desNH2-Tyr1,D-Lys12,Ala15,Nle27] GH-RH(1-28)Agm (MZ-2-57); [desNH2-Tyr1,Ala15,D-Lys21,Nle27] GH-RH(1-28)Agm (MZ-2-75) and [desNH2-Tyr1, D-Lys12,21, Ala15, Nle27] GH-RH(1-28)Agm (MZ-2-87) showed a potency equivalent to 4.4, 1.9, 1.07 and 1.03 times that of GH-RH (1-29)-NH2, respectively, at 5 min and 5.6, 1.8, 1.9 and 1.8 times higher, respectively, at 15 min. After sc administration, analogs MZ-2-51, MZ-2-57 and MZ-2-75 showed to be 34.3, 14.3 and 10.5 times more potent than the parent hormone at 15 min and 179.1, 88.9 and 45.0 times more active, respectively, at 30 min. In addition, MZ-2-51 had prolonged GH-releasing activity as compared to the standard. We also compared the activity of MZ-2-51 and MZ-2-57 with their homologous L-Arg and D-Arg analogs [desNH2-Tyr1,Ala15,Nle27] GH-RH(1-29)-NH2 (MZ-2-117), [des-NH2Tyr1,D-Lys12, Ala15, Nle27] GH-RH(1-29)NH2 (MZ-2-123) and [desNH2-Tyr1,D-Lys12,Ala15, Nle27,D-Arg29] GH-RH(1-29)NH2 (MZ-2-135) after intramuscular (im) injection. MZ-2-51 induced a somewhat greater GH release than MZ-2-117 at 15 min, both responses being larger than the controls (p less than 0.01) at 15 and 30 min. MZ-2-57, MZ-2-123 and MZ-2-135 given i.m. were able to stimulate GH release only at 15 minutes (p less than 0.05). Animals injected i.m. with MZ-2-51, but not with MZ-2-117, showed GH levels significantly higher than the control group (p less than 0.05) at 60 min. GH-RH(1-29)NH2 had low activity intramuscularly when tested at a dose of 2.5 micrograms. No toxic effects were observed after the iv administration of 1 mg/kg of Agm GH-RH analogs. These results indicate that our Agm analogs are active iv, sc and im and that the substitutions made in these compounds produce increased and prolonged GH releasing activity. These analogs, especially MZ-2-51, should be useful for clinical and veterinary purposes.

将生长激素释放激素（GH - RH）的胍丁胺类似物经静脉（iv）和皮下（sc）注射给予戊巴比妥麻醉的雄性大鼠后，将其效果与GH - RH(1 - 29)-NH₂进行比较。静脉注射后，类似物[desNH₂-Tyr¹,Ala¹⁵,Nle²⁷] GH - RH(1 - 28)Agm（MZ - 2 - 51）；[desNH₂-Tyr¹,D - Lys¹²,Ala¹⁵,Nle²⁷] GH - RH(1 - 28)Agm（MZ - 2 - 57）；[desNH₂-Tyr¹,Ala¹⁵,D - Lys²¹,Nle²⁷] GH - RH(1 - 28)Agm（MZ - 2 - 75）和[desNH₂-Tyr¹, D - Lys¹²,²¹, Ala¹⁵, Nle²⁷] GH - RH(1 - 28)Agm（MZ - 2 - 87）在5分钟时显示出的效力分别相当于GH - RH (1 - 29)-NH₂的4.4、1.9、1.07和1.03倍，在15分钟时分别高5.6、1.8、1.9和1.8倍。皮下给药后，类似物MZ - 2 - 51、MZ - 2 - 57和MZ - 2 - 75在15分钟时显示出比母体激素强34.3、14.3和10.5倍的效力，在30分钟时分别活性高179.1、88.9和45.0倍。此外，与标准品相比，MZ - 2 - 51具有延长的GH释放活性。我们还比较了MZ - 2 - 51和MZ - 2 - 57与其同源的L - Arg和D - Arg类似物[desNH₂-Tyr¹,Ala¹⁵,Nle²⁷] GH - RH(1 - 29)-NH₂（MZ - 2 - 117）、[des - NH₂Tyr¹,D - Lys¹², Ala¹⁵, Nle²⁷] GH - RH(1 - 29)NH₂（MZ - 2 - 123）和[desNH₂-Tyr¹,D - Lys¹²,Ala¹⁵, Nle²⁷,D - Arg²⁹] GH - RH(1 - 29)NH₂（MZ - 2 - 135）肌肉注射后的活性。MZ - 2 - 51在15分钟时诱导的GH释放比MZ - 2 - 117略多，在15和30分钟时两种反应均大于对照组（p小于0.01）。肌肉注射的MZ - 2 - 57、MZ - 2 - 123和MZ - 2 - 135仅在15分钟时能够刺激GH释放（p小于0.05）。肌肉注射MZ - 2 - 51的动物在60分钟时GH水平显著高于对照组（p小于0.05），而注射MZ - 2 - 117的动物则不然。以2.5微克的剂量进行测试时，GH - RH(1 - 29)NH₂肌肉注射活性较低。静脉注射1mg/kg的胍丁胺GH - RH类似物后未观察到毒性作用。这些结果表明，我们的胍丁胺类似物经静脉、皮下和肌肉注射均有活性，并且这些化合物中的取代导致GH释放活性增加和延长。这些类似物，尤其是MZ - 2 - 51，应可用于临床和兽医目的。