Introduction

Discovery of the Growth Hormone Releasing Peptides (GHRPs)

In 1977, C.Y. Bowers and his coworkers at Tulane University reported a series of synthetic peptide analogs of Leu- and Met-enkephalins that specifically released growth hormone from the pituitary but possessed no opioid activity (1). However, this pioneering work was overshadowed a few years later by the discovery of an endogenous peptide hormone—growth hormone releasing hormone (GHRH)—as one of two hypothalamic peptides, in addition to the inhibitory peptide hormone somatostatin, known to regulate the release of GH from the pituitary (2-4).

Bowers continued to explore the structure-activity relationships of his early synthetic growth hormone releasing peptides (generally referred to as GHRPs). The hexapeptide GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) emerged as an early benchmark and was shown to be an extremely potent and safe GH secretagogue (GHS) in animals and in humans (5-9). Interestingly, GHRP-6 was shown not only to release GH from the pituitary via a mechanism distinct from the natural regulator GHRH, but also in fact acted synergistically with GHRH to release GH. Whereas GHRH activates protein kinase A via cAMP accumulation, GHRP-6 and its peptidomimetics (vide infra) activates phospho-

From: Human Growth Hormone: Research and Clinical Practice Edited by: R. G. Smith and M. O. Thorner © Humana Press Inc., Totowa, NJ

lipase C to liberate the second messengers IP3 and diacylglycerol. The two pathways converge to release GH from an influx of Ca+2 ions through L-type channels (10-12). Recently, the human receptor for GHRP-6 has been identified in the pituitary and hypothalamus and shown to be a unique G-protein coupled receptor with little homology with other known receptors, including the GHRH receptor (13,14). The natural ligand for this new orphan receptor has not yet been identified, but it undoubtedly plays an important role in the regulation of GH.

The availability of recombinant human growth hormone (rhGH) in the mid-1980s led to many clinical investigations of its potential applications (15,16). In addition to the treatment of GH deficient children and adults, rhGH exhibited beneficial effects in the treatment of patients with burns, bone fractures, and Turner's syndrome. Recently, rhGH has shown promise in reversing the catabolic effects of glucocorticoids, chemotherapy, and AIDS and in improving body composition in elderly individuals (17-20). This explosion in potential clinical applications for GH stimulated further research on the GHRP's and their peptidomimetics. More potent analogs of GHRP-6 have been described (Fig. 1) and their clinical evaluation are currently underway (7,21-24). More recently, cyclic peptides and modified tri- to pentapeptides based on the GHRPs were reported by McDowell et al. (25) to exhibit potent GH releasing activity. Although low oral bioavailability (<1%) has been reported for all the GHRP's to date, they have clearly established that a relatively small molecule (MW <1000 kDa), administrated orally, can stimulate the release of endogenous GH and thus may offer a practical alternative to subcutaneous treatment with costly rhGH.

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