GROWTH HORMONE-RELEASING PEPTIDES AND THEIR ANALOGS

Growth hormone-releasing peptides (GHRPs) are a series of hepta (GHRP- 1)- and hexapeptides (GHRP-2, GHRP-6, Hexarelin) that have been shown to be effective releasers of GH in animals and humans. More recently, a series of nonpeptidyl GH secretagogues (L-692,429, L-692,585, MK-067 7) were discovered using GHRP-B as a template. Some cyclic peptides as well as penta-, tetra-, and pseudotripeptides have also been describe d. This review summarizes recent developments in our understanding of the GHRPs, as well as the current nonpeptide pharmacologic analogs. GH RPs and their analogs have no structural homology with GHRH and act vi a specific receptors present at either the pituitary or the hypothalam ic level. The GKRP receptor has recently been cloned and it does not s how sequence homology with other G-protein-coupled receptors known so far. This evidence strongly suggests the existence of a natural GHRP-L ike ligand which, however, has not yet been found. Although the exact mechanism of action of GHRPs has not been fully established, there is probably a dual site of action on both the pituitary and the hypothala mus, possibly involving regulatory factors in addition to GHRH and som atostatin. Moreover, the possibility that GHRPs act via an unknown hyp othalamic factor (U factor) is still open. The marked GH-releasing act ivity of GHRPs is reproducible and dose-related after intravenous, sub cutaneous, intranasal, and even oral administration. The GH-releasing effect of GHRPs is the same in both sexes, but undergoes age-related v ariations. It increases from birth to puberty and decreases in aging. The GH-releasing activity of GHRPs is synergistic with that of GHRH an d not affected by opioid receptor antagonists, while it is only blunte d by inhibitory influences that are known to nearly abolish the effect of GHRH, such as neurotransmitters, glucose, free fatty acids, glucoc orticoids, rhGH, and even exogenous somatostatin. GKRPs maintain their GH-releasing effect in somatotrope hypersecretory states, such as acr omegaIy, anorexia nervosa, and hyperthyroidism. On the other hand, GHR Ps and their analogs have been reported to be effective in idiopathic short stature, in some situations of GH deficiency, in obesity, and in hypothyroidism, while in patients with pituitary stalk disconnection and in Gushing's syndrome the somatotrope responsiveness to GHRPs is a lmost absent. A potential role in the treatment of short stature, agin g, catabolic states, and dilated cardiomyopathy has been envisaged. (C ) 1998 Academic Press.