Evaluation of in vivo [corrected] biological activity of new agmatine analogs of growth hormone-releasing hormone (GH-RH)

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.