Showing papers on "Growth hormone secretagogue published in 1994"
TL;DR: Molecular modeling of the structurally diverse GH secretagogues, L-692,429 and GHRP-6, was performed and shows the seven-membered benzazepinone skeleton to be preferred.
Abstract: The 3-substituted benzazepinone, L-692,429 (compound 1), is the prototype compound of a novel class of compounds that stimulate release of growth hormone (GH). The molecule evolved from efforts to identify a non-peptide mimic of the growth hormone-releasing hexapeptide, GHRP-6. Compound 1 is prepared by sequential attachment of dimethyl-beta-alanine and 2'-biphenylyltetrazole side chains to a chiral 3-aminobenzolactam nucleus. Comparison of the biological activity of 1 with the corresponding six- and eight-membered lactam analogs shows the seven-membered benzazepinone skeleton to be preferred. Molecular modeling of the structurally diverse GH secretagogues, L-692,429 and GHRP-6, was performed.
100 citations
TL;DR: When L-692,585 was administered once daily for 14 consecutive days at 0, 0.01 or 0.10 mg/kg to each of 6 dogs, peak plasma GH levels and total GH release on days 1, 8 and 15 significantly increased in a dose-dependent manner, and no desensitization was evident.
Abstract: L-692,585 is a 2-hydroxypropyl derivative of L-692,429, both novel non-peptidyl growth hormone (GH) secretagogues. The effects of single and repeated intravenous administration of L-692,585 on serum or plasma GH and other hormones in beagles were evaluated. In a balanced 8-dog dose-ranging study, compared to the saline control with a mean (+/- S.E.M.) after-dose serum GH peak of 6.1 +/- 1.3 ng/ml, L-692,585 significantly increased (P < 0.05) peak GH concentrations 4.3-fold (32.5 +/- 7.0 ng/ml) at a dose of 0.005 mg/kg, 7-fold (49.4 +/- 10.6 ng/ml) at a dose of 0.02 mg/kg, and 21-fold (134.3 +/- 29.0 ng/ml) at a dose of 0.10 mg/kg. Total GH release, expressed as area under the curve, showed a similar dose-dependent increase. Peak GH levels were recorded at 5 or 15 min after dosing with the levels returning to near baseline by 90 min. Serum cortisol levels were increased above saline control levels in a dose-dependent manner; however, the increases were modest compared to the GH increases. Based on peak responses and total GH release, L-692,585 was 10- to 20-fold and 2- to 2.5-fold more potent than L-692,429 and the growth hormone releasing peptide, GHRP-6, respectively. When L-692,585 was administered once daily for 14 consecutive days at 0, 0.01 or 0.10 mg/kg to each of 6 dogs, peak plasma GH levels and total GH release on days 1, 8 and 15 significantly increased in a dose-dependent manner, and no desensitization was evident.(ABSTRACT TRUNCATED AT 250 WORDS)
92 citations
TL;DR: Deconvolution analysis demonstrated that the increase in serum GH concentrations stimulated by L and GHRH resulted from enhanced GH secretion rates, with no change in the half-life of GH disappearance.
Abstract: L-692,429 (L), a novel nonpeptide mimic of GH-releasing peptide (GHRP), is a potent GH secretagogue in animals and young men. To assess the safety and efficacy of L in stimulating GH release in healthy older men and women, 16 subjects were admitted to a randomized, double blind, cross-over comparison of i.v. administered placebo, GH-releasing hormone [GHRH-(1-29)-NH2; 1 microgram/kg] and two doses of L (0.2 and 0.75 mg/kg). Blood samples were obtained at 5-min intervals for 60 min before and 240 min after each dose for measurement of GH; cortisol, PRL, and insulin-like growth factor-I (IGF-I) were measured less frequently. Peak and integrated GH concentrations increased significantly after L in a dose-dependent manner. Responses to L at either dose were significantly greater than the response to GHRH: peak GH responses in older men and women were (mean +/- SE; micrograms per L): after placebo, 1.2 +/- 0.2; L (0.2 mg/kg), 16.5 +/- 1.8; L (0.75 mg/kg), 32.2 +/- 3.9; and GHRH, 7.6 +/- 1.3 (P < 0.05, L vs. pl...
85 citations
TL;DR: In this paper, the amino acid sidechain of L-692,429, the prototype of a novel class of benzolactam growth hormone secretagogues, has been investigated.
17 citations
TL;DR: 2′-carboxamide 22 and N-2-hydroxypropyl tetrazoles 7a,b were identified as neutral pharmacophores with similar potency to that of the acidic 2′-tetrazole.
12 citations
01 Jan 1994
TL;DR: The experimental observations suggested a causal relationship between anatomical senescence and GH insufficiency, and aberrant patterns of spontaneous GH secretion and low serum GH concentrations during aging did not necessarily represent loss of GH efficacy.
Abstract: Degenerative changes in body composition characterized by reduced muscle and bone mass decrease physical performance in the elderly. These decremental somatic changes correlate with reduced serum growth hormone (GH) concentrations. Limited availability of cadaver-derived hormone before the advent of recombinant gene technology precluded testing the functional relationship between GH deficiency and senescence. However, when bioengineered GH became available for experimentation, its administration to old men significantly increased serum IGF-I concentrations, urinary nitrogen retention, body weight gain, lean body mass, bone density, renal function, and improved quality of life (1–3). Thus, aberrant patterns of spontaneous GH secretion and low serum GH concentrations during aging (4–7) did not necessarily represent loss of GH efficacy. Furthermore, the experimental observations suggested a causal relationship between anatomical senescence and GH insufficiency (3, 4, 8, 9).
10 citations
8 citations