The discovery of novel GHRPs and the comparison of their structure and function has been the subject of much recent experimentation, debate and discussion in both academic laboratories and within the pharmaceutical industry. However, despite the progress in GHRP chemistry and new GHRP receptor characterisation the physiology, pharmacology and biology of the GHRP system is still very poorly understood. This paucity of biological knowledge has in particular affected medicinal chemistry projects aimed at exploiting the activity of the GHRPs for medical benefit. This lack of biological knowledge has impacted the choice of assays for testing for GH-releasing activity and testing for the specificity of pituitary hormone release.
There is also very limited published data on GHRP efficacy in animals, beyond data on GH release, and because of this there is also a similar paucity of data on the optimal or most efficacious pattern of GHRP exposure. This lack of efficacy data in animals, and appropriate models for testing molecules and delivery patterns, and therefore a lack of information on optimal routes and patterns of administration, has perhaps contributed to the development of GHRPs in humans being much slower than one would have originally predicted. Recently, a very promising orally active and potent GHRP, MK-677, failed to show a maintained acceleration of statural growth in children. This disappointing result may be another symptom of our poor understanding of the parameters governing GHRP efficacy and therefore our inability to translate knowledge of structure-activity relationships, found using in vitro systems, into molecules useful as therapeutic agents. It is possible that GHRP structure-function studies need to be reassessed, especially in terms of the elements needed for a successful drug and clinical development programme.
This review therefore describes the factors that affect GHRP efficacy in vivo in animals and in humans and identifies the issues that need to be considered in current and future structure-function studies of GHRPs. A key question in the design of an integrated GHRP biology and chemistry programme is which activity of the GHRPs should be followed, and therefore which assay systems should be used? The answer to the question, of which activity to follow, is not obvious. This can be seen from different laboratories using different assays to measure GHRP activity. One reason for this difference is that at one time it was beUeved that the GHRPs were similar, or at least equivalent in terms of their activity, to growth hormone releasing factor (GRF) in that their major site of action, or even their sole site of action, was at the level of the pituitary gland. This activity on the pituitary gland was thought to be due to a direct effect of GHRP on somatotrophs that was independent of the hypothalamic releasing factors GRF and somatostatin. This was based on GHRP having direct GH-releasing effects in vitro on cultured somatotrophs.
In contrast early in vivo data suggested that the GH-releasing activity of GHRP injections was dependent on GRF and somatostatin activity. This experimental data, that the majority of the GH-releasing activity of GHRP in vivo depended on it having direct hypothalamic activity on the GRF and somatostatin systems, was met with some doubt. The effects of GHRP in vivo are complex and to account for this it has been suggested that an additional hypothalamic factor (U factor) is released by GHRP in vivo. But in the early 1990s doubt existed regarding the relative importance, and relevance, of the pituitary and hypothalamic activities of GHRPs. This, of course, affected the choice of the appropriate assays, in vitro or in vivo, with which to measure GHRP activity. These debates, in turn, clearly affected the choice of assays to use in a chemistry programme for GHRP drug design. Some chemistry programmes appear to have chosen to use only in vitro assays based on the direct GH-releasing activity of GHRPs on pituitary cells in culture. Other programmes routinely used in vivo assays, or a combination of both methods. The eariiest studies of GHRP structure-function showed the importance of the choice of models for measuring GHRP activity.
For example, the initial studies by Bowers, of synthetic GHRP peptides, showed that structure-activity relationships in vitro did not necessarily translate into in vivo activity. The largest subsequent studies of GHRP structure-activity seem to have used routinely only an in vitro pituitary assay of GH release. It remains unclear whether the large number of compounds described in this work would show similar activity in vitro and in vivo. This data shows a very poor relationship between in vitro and in vivo potency. The in vivo data from such comparisons, despite being based on intravenous injections, will be confounded by different classes of compounds having different pharmacokinetics or biodistribution rather than having different receptor binding. Despite such a caveat, some of the scatter probably reflects a structurally specific and mechanism-based difference in GHRP activity. It seems clear that the use of different but complementary assays of biological activity is of value in dissecting the structure-activity relationships of GHRPs. A biological basis for these differences can now be established, as GHRP receptors are now being discovered, but it will remain necessary to confirm the activity of GHRPs in vivo.
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1. Regulation of synthesis and secretion
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