Pharmacological profile of a new orally active growth hormone secretagogue, SM-130686.
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 GH-releasing hormone antagonist. SM-130686 dose-dependently 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.
Nagamine
J
J
Sumitomo Pharmaceuticals Co. Ltd, Discovery Research Laboratories II, 1-98 Kasugade Naka 3-chome, Konohana-ku, Osaka 554-0022, Japan.
Nagata
R
R
Seki
H
H
Nomura-Akimaru
N
N
Ueki
Y
Y
Kumagai
K
K
Taiji
M
M
Noguchi
H
H
D000284:Administration, Oral; D000818:Animals; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005021:Ethylamines / Q000494:pharmacology*; D005260:Female; D054439:Ghrelin; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D036361:Peptide Hormones; D010455:Peptides / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D015430:Weight Gain / Q000187:drug effects
D005021:Ethylamines; D054439:Ghrelin; D007211:Indoles; D036361:Peptide Hormones; D010455:Peptides; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; C443685:SM 130686; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone