Growth hormone response in man to L-692,429, a novel nonpeptide mimic of growth hormone-releasing peptide-6.

Abstract

L-692,429, a substituted benzolactam, is a novel nonpeptide mimic of the GH secretagogue, GH-releasing peptide-6. The safety and GH secretory activity of L-692,429 (0.001-1.0 mg/kg, i.v.) were investigated in 24 healthy nonobese young (18-26 yr old) male volunteers who demonstrated a GH response of 7 micrograms/L or more after 1 microgram/kg, i.v. GH-releasing hormone [GH-releasing hormone-(1-29)NH2]. L-692,429 was administered as a 15-min iv infusion in an incremental dose, double blind, placebo-controlled, alternating panel fashion to 3 panels of 8 subjects each. Dose-dependent GH secretion was observed with a threshold dose of 0.05 mg/kg (4 of 6 subjects responded with peak GH > 7 micrograms/L), and 0.2 mg/kg produced a response in all 14 subjects tested (mean +/- SE peak GH, 41.0 +/- 6.3 micrograms/L). The maximum dose of 1.0 mg/kg L-692,429 resulted in a pronounced GH response (peak GH, 82.5 +/- 14.9 micrograms/L; n = 8). The GH peak was seen 30-45 min after initiation of the infusion. Small transient increases in cortical and PRL were observed (increases in cortical averaged 182.1 +/- 33.1 nmol/L and peak PRL was 21 +/- 2.6 micrograms/L after 1.0 mg/kg L-692,429, respectively), whereas no significant changes occurred in LH, FSH, TSH, insulin, or glucose concentrations. Plasma pharmacokinetic analysis revealed dose-related increases in plasma concentrations of L-692,429 and a half-life of 3.8 +/- 0.2 (+/- SE) h, a plasma clearance of 214 +/- 67 mL/min, and a steady state volume of distribution of 14.2 +/- 4.8 L. Facial flushing or a warm sensation were reported in 4 subjects, primarily at dose levels of 0.2 mg/kg L-692,429 or more, but no other clinical or laboratory adverse experiences appeared related to drug treatment. L-692,429, synthesized as a specific nonpeptide mimic of GH-releasing peptide-6, is thus a well tolerated, highly effective, and selective GH secretagogue in man.

Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue.

“…Thus, L-163,191 is a selective GH secretagogue with the exception of modest increases in cortisol. Similar small elevations of cortisol were reported with L-692,429 in dogs (22) and in humans (9,10). Also, some cortisol increases have been reported with GHRP-6 in humans (28).…”

“…Furthermore, the nonpeptide L-692,429 (MK-0751) ( Fig. 1) has been shown to elevate GH in young male volunteers (9) and in healthy older subjects (10) with only small transient increases in cortisol and prolactin. Thus, the effectiveness of the GHRP-6 mechanism has been established in the clinic with peptides as well as a nonpeptide.…”

Unexpected Activation of Pituitary-Adrenal Axis in Healthy Young and Elderly Subjects during Somatostatin Infusion

“…The latter, in turn, would be transduced into an increased secretion of ACTH for the release of, or in synergy with, one or more of the endogenous ACTH secretagogues, such as corticotropin-releasing hormone or arginine-vasopressin. In this context, it has been shown, recently, that changes in HPA function might reflect, at least in part, the ACTH-promoting activity [25, 26, 27] of the still elusive endogenous ligand(s) for the recently cloned GHRP receptor [28, 29]. In our study, this might have occurred in response to the SRIH-induced fall in circulating GH levels, and viewed as an attempt to restore normal GH secretion.…”

Effect of growth hormone secretagogue LY444711 on IGF-1, growth hormone, and cortisol levels in beagle dogs after one and seven daily oral doses

“…Although the mechanism for this increase is not known, secretagogues are hypothesized to increase ACTH release from the pituitary, resulting in elevation of cortisol levels [Arvat et al, 1999]. Similar to the obser- vations of a lack of sustained effect of GH secretagogues on mean cortisol levels in dogs, there has been no evidence of sustained elevation of cortisol secretion in humans exposed to GH secretagogues [Copinschi et al, 1996;Gertz et al, 1993].…”