ABSTRACT
Over 4 years ago it was reported that, in addition to eliciting growth hormone (GH) release from the anterior pituitary gland, GHRP-6, specifically induced Fos-like immunoreactivity (Fos-LI) within the rat hypothalamic arcuate nucleus, in the region of the nucleus thought to contain growth hormone-releasing hormone (GHRH) neurons (1). As the expression of Fos-LI, and its progenitor cfos, have been used extensively within neuroendocrine systems to map cellular activation, this observation was taken to indicate that GHRP-6 acts centrally to increase the neuronal activity of arcuate nucleus GHRH neurons. Subsequently, colocalization studies have demonstrated that GHRP-6 induces c-fos mRNA in an appreciable proportion of arcuate nucleus GHRH neurons (2). Similarly, systemic injection of GHRP-6 increases the electrical activity of identified neuroendocrine arcuate nucleus neurons and stimulates GHRH release into the hypophysial portal blood (3,4). The possibility that GHRP-6 could influence GH release at both central and peripheral sites gave this secretagogue an enormous therapeutic potential. This potential was tempered by the fact that, as a peptide, GHRP-6 possesses a limited oral bioavailability, and this led to the generation of a range of orally available GH secretagogues (GHSs). Initial attempts
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at GH secretagogue generation utilized a benzolactam core as a structural template (e.g., L-692,429) and, although these compounds possessed GH secretory activity, their oral efficacy was not greatly enhanced. However, a new structural class of compounds, based on a spiroindoline core, has both GH secretory activity and oral bioavailability. Structural refinement of these compounds has led to the synthesis of the potent, orally active GH secretagogue, MK-0677 (5).
