A NOVEL NON-PEPTIDYL GROWTH-HORMONE SECRETAGOGUE

Direct screening of preselected compounds in a rat primary pituitary c ell culture assay, followed by chemical modification of selected pharm acophores led to the identification of a novel non-peptidyl class of G H secretagogues (substituted benzolactams). The prototype compound of this class, L-692,429, stimulated GH release from rat primary pituitar y 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-rel easing 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 muM. GH r elease induced by L-692,429 was inhibited by somatostatin as well as b y GHRP-6 and substance P antagonists but not by GRF or opiate antagoni sts. L-692,400, which is structurally related to L-692,429 but biologi cally inactive, inhibited GH response not only to L-692,429 but also G HRP-6. Like GHRP-6, L-692,429 alone had no effect on intracellular cAM P 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 pres ented 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 adre nocorticotropin. These results demonstrate that L-692,429 is the first non-peptidyl secretagogue which has a direct and specific effect on G H release from rat pituitary cells, and its action appears to be media ted through the same receptor and signalling pathway as GHRP-6.