Conclusions

The secondary structure of the GHRH sequence(s) has now been well-elucidated and appears to consist of an amphiphilic a-helical conformation along the whole chain. Advantage has been taken of this to synthesize a great number of more potent analogs in which the helix is stabilized by various means. One method employs the use of Ala/Aib substitution for many of the amino acids in the chain, including several with functional side chains. In addition, this design approach allows for significant chain shortening to be carried out on the C-terminus of GHRH(1-29)NH2 with good retention of in vitro potency. This results in structures that are much simpler than the parent peptide and which may be of some use in molecular modeling of the peptide with its receptor. These simplified analogs are also considerably easier and more cost efficient to prepare on a large scale. Also, it is expected that these design approaches will be of similar value when applied to other members of this family of peptides.

Although a number of analogs exist with significantly improved potency in the rat, those that have been carried through to human studies have so far produced disappointing results. However, as more and more proteolytic sites are stabilized along the sequence, it might be expected that significantly more potent and longer-acting analogs will even tually prove useful clinically. Quite potent GHRH receptor antagonists now exist; however, a clinical utility for this type of compound remains to be demonstrated, given the efficacy of somatostatin analogs in blocking GH release. With respect to somatostatin, the recent discovery (64) of potent type 2 receptor antagonists could have profound clinical consequences, because they might be used for GH stimulation either alone or in combination with GH, GHRH, or GHRP. This is because GH tone is generally under strong negative control by endogenous somatostatin and somatostatin release can actually be stimulated by these agents.

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