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- W2115801893 startingPage "346" @default.
- W2115801893 abstract "The GH secretagogues (GHS) were developed by reverse pharmacology. The objective was to develop small molecules with pharmacokinetics suitable for once-daily oral administration that would rejuvenate the GH/IGF-I axis. Neither the receptor nor the ligand that controlled pulse amplitude of hormone release was known; therefore, identification of lead structures was based on function. I reasoned that GH pulse amplitude could be increased by four possible mechanisms: 1) increasing GHRH release; 2) amplifying GHRH signaling in somatotrophs of the anterior pituitary gland; 3) reducing somatostatin release; and 4) antagonizing somatostatin receptor signaling. Remarkably, the GHS act through all four mechanisms to reproduce a young adult physiological GH profile in elderly subjects that was accompanied by increased bone mineral density and lean mass, modest improvements in strength, and improved recovery from hip fracture. Furthermore, restoration of thymic function was induced in old mice. The GHS receptor (GHS-R) was subsequently identified by expression cloning and found to be a previously unknown G protein-coupled receptor expressed predominantly in brain, pituitary gland, and pancreas. Reverse pharmacology was completed when the cloned GHS-R was exploited to identify an endogenous agonist (ghrelin) and a partial agonist (adenosine); ghsr-knockout mice studies confirmed that GHS are ghrelin mimetics." @default.
- W2115801893 created "2016-06-24" @default.
- W2115801893 creator A5091876557 @default.
- W2115801893 date "2005-04-06" @default.
- W2115801893 modified "2023-09-29" @default.
- W2115801893 title "Development of Growth Hormone Secretagogues" @default.
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