When Shakespeare wrote that the "Chief nourisher in life's feast" issleep, the bard was 400 years ahead of his time.

It's shortly after the onset of sleep that the pituitary gland secretesmost of its daily dollop of growth hormone. That hormone, a.k.a.somatotropin, nourishes protein synthesis throughout the body, andthroughout life.

In the young, growth hormone (GH) promotes maturation of theskeleton, most visibly the arm and leg long bones. In the aged, a 1990study by endocrinologist Daniel Rudman at the University of Chicagoshowed, recombinant human GH improved the quality of life forotherwise healthy men aged 61 to 81.

In those elderly subjects, one of the peptides that carries out GH'sfunctions, insulin-like growth factor (ILGF), was deficient.

Rudman reported that giving thrice-weekly injections of GH to thosemen restored their ILGF levels, increased their lean body mass anddecreased their adipose tissue, while enhancing skin thickness and thebone density of their vertebrae.

In today's Science, endocrinologists P. Michael Conn and CyrilBowers observed of such aging patients, "Clearly, a drug that wouldcause release of the individual's own growth hormone would bepreferable to thrice-weekly self-administration, especially if a versionwith oral activity were available."

Just such a drug is on the drawing board of the Merck ResearchLaboratories, in Rahway, N.J.

The genesis of this quest, Conn told BioWorld Today, goes back to1984 when Bowers, at Tulane University Medical School in NewOrleans, "developed a synthetic hexapeptide that causes release ofgrowth hormone from the pituitary gland." Bowers noted at the timethat his synthetic growth hormone release peptide (GHRP) acted at areceptor different from that of the natural GH releasing hormone.

Conn is on the faculty of Oregon Health Sciences University, and ispresident of the Endocrine Society, based in Bethesda, Md.

"It had been recognized for years," he said, "that opiates can causerelease of GH. Indeed," he pointed out, "certain peptide analogues ofthe opiate Met-enkephalin [see BioWorld Today, July 27, 1996, p. 1]lack opiate activity but still cause GH release.

"The fact that Bowers was able to separate the GH receptor activityfrom the opiate," Conn continued, "was very significant, andsuggested there were two unrelated pathways. These things wereunrelated but serendipitous."

Bowers participated in licensing his synthetic peptide to a series ofdrug companies, including the then Beckman Bioproducts, and later,Merck Research Laboratories.

The fact that this synthetic product appeared to act at a differentreceptor than the known natural GH releasing hormone suggested toMerck and others that it was mimicking a second, unknown, receptor,which also triggered the release.

That second receptor is no longer unknown. In today's Science, 32Merck co-authors report finding "A receptor in pituitary andhypothalamus that functions in growth hormone release."

They found it by "reverse drug discovery," a term Conn coined.

"Until recently," he and Bowers observed in their Science"Perspective" accompanying the Merck paper, "the typical pathleading to the development of a drug has been to identify the activecompound and then to make analogues that recognize the target(usually a receptor or an enzyme)."

Instead, the Merck group "followed a different route." They"identified a potential lead drug before the identification of either theendogenous active compound or the receptor."

Conn concluded: "Identification of the receptor unequivocallyestablishes a novel target of action for this drug class. It could leadscientists to develop a growth-hormone-releasing pill that is cheaperand easier to use than administration of GH itself."

Medical geneticist Lex Van der Ploeg, the Science paper's principalauthor, is senior director at Merck for genetics and molecularbiology. He told BioWorld Today where the company's ongoingproduct research stands:

"The cloned receptor now is being used to identify the naturalhormone that it is responsive to. And we are searching for thepresumed natural ligand that must exist in the human body for thisreceptor."

Van der Ploeg continued: "That will further advance and highlightthe pathway of these synthetic peptides. Also, the Merck compoundsthat activate this pathway are based on orally active drugs that peoplecan take.

"That's the essence of what's being done." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.