An evaluation of intravenous, subcutaneous, and in vitro activity of new agmatine analogs of growth hormone-releasing hormone hGH-RH(1-29)NH₂

The effects of new Agmatine (Agm) analogs of human growth hormone-releasing hormone (GH-RH) were compared to GH-RH(1-29)NH₂ and to (D-Ala²)GH-RH(1-29)NH₂ after intravenous (IV) and subcutaneous (SC) administration to pentobarbital-anesthetised male rats and in vitro using superfused rat pituitary cell system. After IV administration, the analogs: (D-MeAla², Nle²⁷)GH-RH(1-28)Agm(JG-75), (desamino-Tyr¹, D-Ala², Nle²⁷)GH-RH(1-28)Agm(JG-77), (D-Ala², Nle²⁷)GH-RH(1-28)Agm(JG-73) and (D-Ala²)GH-RH(1-29)NH₂ showed a potency 2.6-3.9 times greater than GH-RH(1-29)NH₂ at 5 min and 1.6-2.7 times higher at 15 min. After SC administration these analogs were 30-74 times more potent than GH-RH(1-29)NH₂. The ratio between the IV and SC GH-releasing activity of the analogs ranged from 2 to 5, while GH-RH(1-29)NH₂ was about 50 times more active IV than SC. This indicates that 20-50% of the analogs can be absorbed from SC tissues, but only 2% of GH-RH(1-29)NH₂. The in vitro activity of the agmatine analogs on GH release closely paralleled their IV potency and was 2.8-3.9 times greater than that of GH-RH(1-29)NH₂. No significant difference in potency was found between (D-Ala²)GH-RH(1-29)NH₂ and JG-75 after IV administration and in vitro, although JG-75 contained only 28 amino acids. We conclude that the reason for the large discrepancies between the previously reported activities of (D-Ala²)GH-RH(1-29)NH₂ was simply due to the different ways of administration of this analog, SC vs IV, and not to species specificity. The replacement of Arg²⁹ by Agmatine in (D-Ala², Nle²⁷)GH-RH(1-29)NH₂ causes a 3 fold increase in SC potency, but the replacement of D-Ala² with D-MeAla² reduces the SC, but not the IV and in vitro activity in half.