Pharmacological profile of a new orally active growth hormone secretagogue, SM-130686

Abstract

SM-130686, an oxindole derivative, is a novel orally active GH secretagogue (GHS) which is structurally distinct from previously reported GHSs such as MK-677, NN703 and hexarelin. SM-130686 stimulates GH release from cultured rat pituitary cells in a dose-dependent manner. Half-maximum stimulation was observed at a concentration of 6⋅3 3⋅4 nM. SM-130686-induced GH release was inhibited by a GHS antagonist, but not by a GHreleasing hormone antagonist. SM-130686 dosedependently inhibited the binding of radiolabeled ligand, 35 S-MK-677, to human GHS receptor 1a (IC 50 =1⋅2 nM). This indicates that SM-130686 stimulates GH release through the GHS receptor. The effect of a single oral administration of SM-130686 on GH release in pentobarbital-anesthetized rats was studied. After treatment with 10 mg/kg SM-130686, plasma GH concentrations measured by radioimmunoassay significantly increased, reaching a peak at 20-45 min, and remained above baseline during the experimental period (60 min). The anabolic effect of repetitive SM-130686 administration was studied in rats. Rats received 10 mg/kg SM-130686 orally twice a day and were weighed every day for 9 days. At day 9 there was a significant increase in both the body weight and the fat free mass (19⋅5 2⋅1 and 18⋅1 7⋅5 g respectively). Serum IGF-I concentration was also significantly elevated 6 h after the last dose of SM-130686. An endogenous GHS ligand for the GHS receptor has recently been identified from stomach extract and designated as ghrelin. The GH-releasing activity in vitro relative to ghrelin (100%) was about 52% for SM-130686. It is likely that SM-130686 is a partial agonist for the GHS receptor.In summary, we describe here an orally active GHS, SM-130686, which acts through the GHS receptor. Repetitive administration of SM-130686 to rats, similar to repetitive administration of GH, significantly increased the fat free mass by an amount almost equal to the gain in body weight.

Synthesis and Pharmacological Profile of an Orally-Active Growth Hormone Secretagogue, SM-130686

“…It is of interest that small molecules such as SM-130686 and MK-677 can replace a larger peptide, ghrelin, bound to its specific receptor, although small molecules are used in higher concentrations than ghrelin. In addition, we have confirmed that the binding affinities of SM-130686 to 50 other receptors, including GHRH and somatostatin receptors, are lower than that with GHS-R [24].…”

“…In order to study the specificity of SM-130686 action through the GHS-R, several antagonists were used concomitantly with SM-130686 in cultured primary rat pituitary cells. SM-130686-induced GH release was blocked by GHS-R antagonists ([D-Arg 1 , D-Phe 5 , D-Trp 7,9 , Leu 11 ]-substance P), but not by GHRH antagonists ([N-acetyl-Try 1 , D-Arg 2 ]-hGHRH(1-29)NH 2 ) [24]. Since the binding affinities of SM-130686 with 50 other receptors were lower than that with the GHS-R as briefly mentioned above, these data indicate that SM-130686 stimulates GH release by specifically acting on the GHS-R.…”

A novel GH secretagogue, A233, exhibits enhanced growth activity and innate immune system stimulation in teleosts fish

“…In adult rats, GHRP6 also increased body weight (Svensson et al 2000) as well as other GHSR agonists, like SM-130686 administered orally (Nagamine et al 2001) and BIM-28131 administered by s.c. injection (Strassburg et al 2008). It has been recently reported that GHSR1a agonist, a pentapeptide with D-amino acids, promotes weight gain in rats, by i.p.…”

Growth Hormone Secretagogues

“…SM-130686 has potent activity and a good pharmacokinetic profile in rats and might be a partial agonist for GHS-R 1a [37]. Repetitive administration of SM-130686 to rats, similar to repetitive administration of GH, significantly increased the fat free mass by an amount almost equal to the gain in body weight.…”