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When the isolation (from human pancreatic growth hormone [GH]-secreting tumors) and structures of several forms of growth hormone-releasing hormone (GHRH) were first reported (1,2), much surprise was generated by the size of the peptide since all previously sequenced hypothalamic hormones were made up of relatively short amino-acid sequences. Also surprising at the time was the high degree of amino-acid sequence homology between GHRH and members of the quite extensive vasoactive intestinal polypeptide (VIP)/glucagon family of peptides (Fig. 1) all of which were of gastrointestinal or pancreatic origin. There is clearly a common evolutionary pathway, presumably owing to gene duplication, which has resulted in two major branches of this family: GHRH/PACAP, VIP/PHI, and secretin on one hand and glucagon/glucagon-like polypeptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) on the other and these aspects have been reviewed recently (3). As with other known hypothalamic hormones, with the exception of somatostatin, GHRH is highly specific having demonstrable potent biological activity on GH release from the pituitary. However, there are indications that GHRH might also play a peripheral role, for instance in fetal/placental development, reproduction, and immune function (3,4). Indeed, GHRH immunoreactiv-ity has been found not only in the hypothalamus and pituitary but also in pancreas, kidney,

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

Fig. 1. Amino-acid sequences of peptides in the same family as GHRH. Vertical lines indicate where sequence shortening can be effected with little loss of potency. Basic residues are emphasized in order to highlight there different spacing from peptide to peptide—this may influence their receptor specificity (see text).

duodenum, lung, testis, ovary, adrenal, heart, and brain (5,6). Although the biological responses, if any, of GHRH at these tissues are far from being fully characterized, the peptide does stimulate pancreatic exocrine secretion in vitro and in vivo (7,8) and weakly interacts with receptors for other GI peptides, particularly VIP (9,10). There is also evidence of GHRH has effects on secretion of other peptides from several cell lines, for instance, stimulation of neurotensin and calcitonin from rat C cells (11). These additional interactions and activities have to be kept in mind during the design of highly potent peptide analogs of GHRH in case unwanted side effects are inadvertently enhanced.

Because a fair amount of structure-activity work had already been performed on the older members of the series, particularly VIP and secretin, it was clear that some previously successful analog design approaches could probably be applied to GHRH. Indeed, it was found (2,12) almost immediately that the 40 or 44 amino-acid chain of GHRH (Fig. 1) could be shortened from the C-terminus until it was similar in length to VIP, secretin, and glucagon. The shortest, fully potent fragment appeared to be GHRH(1-29) (12) and the amidated form of this peptide has provided the basic structure for the vast majority of structure-activity studies that have been reported, largely because synthetic difficulties associated with peptides of this size are minimized. Another useful guide to structural features responsible for receptor binding and/or activation has also been derived from sequence comparisons among animal species. There are reports describing the GHRH structures in rat (13), cow (14), pig (15), sheep (16), and goat (16) and these are shown in Table 1. The greatest sequence difference exists between human and rat GHRH, which has His rather than Tyr in position 1 and a Ser for Asn replacement in positions 8. However, the functional results of this are not great and it is apparent that the high homology between species in the core 1-29 region reflects its importance for high biological potencies in all members of this peptide family.

There is currently much interest in the therapeutic use of agents that increase GH levels in hormone-deficient situations such as short stature children and elderly populations. Clinical studies (17) with growth hormone-releasing factor (GHRF)(1-40) and (1-29) are perhaps relatively disappointing (18) compared to therapy with GH itself, owing to

Table 1 Amino-Acid Sequences

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