title: A novel non-peptidyl growth hormone secretagogue.
abstract: Direct screening of preselected compounds in a rat primary pituitary cell culture assay, followed by chemical modification of selected pharmacophores led to the identification of a novel non-peptidyl class of GH secretagogues (substituted benzolactams). The prototype compound of this class, L-692,429, stimulated GH release from rat primary pituitary cells in a time- and dose-dependent manner with an EC50 value of 60 nM. Under the same conditions, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GH-releasing peptide, GHRP-6) and GH-releasing factor (GRF) had EC50 values of 10(-8) and 5 x 10(-10) M, respectively. L-692,428, the S-enantiomer, of L-692,429, was inactive at a concentration as high as 2 microM. GH release induced by L-692,429 was inhibited by somatostatin as well as by GHRP-6 and substance P antagonists but not by GRF or opiate antagonists. L-692,400, which is structurally related to L-692,429 but biologically inactive, inhibited GH response not only to L-692,429 but also GHRP-6. Like GHRP-6, L-692,429 alone had no effect on intracellular cAMP levels; however, it synergized with GRF to further increase both the accumulation of cAMP and the release of GH. Maximal effects of L-692,429 and GHRP-6 on GH release were comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause an additional GH release when compared with either secretagogue alone. L-692,429 had a small effect on prolactin release but not adrenocorticotropin.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Merck Research Laboratories, Department of Growth Biochemistry and Physiology, Rahway, NJ 07065.
authors.forename: K
authors.initials: K
authors.lastname: Cheng
authors.forename: W W
authors.initials: WW
authors.lastname: Chan
authors.forename: B
authors.initials: B
authors.lastname: Butler
authors.forename: L
authors.initials: L
authors.lastname: Wei
authors.forename: R G
authors.initials: RG
authors.lastname: Smith
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D013006:Growth Hormone / Q000378:metabolism*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D009994:Osmolar Concentration; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013004:Somatostatin / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D001552:Benzazepines; D009842:Oligopeptides; D013777:Tetrazoles; C081455:L 692429; C041048:growth hormone releasing hexapeptide; D013004:Somatostatin; D013006:Growth Hormone; D000242:Cyclic AMP